Treatment of injury of the spinal cord or brain using 4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine

ABSTRACT

A class of substituted phenylpyrimidine compounds are disclosed which are potent inhibitors of the excitatory amino acid, glutamate. Such compounds are useful in the treatment or prevention of a range of CNS disorders including cerebral ischaemic damage and epilepsy.

This is a division of application Ser. No. 07/444,963, filed Dec. 4,1989 now abandoned.

The present invention relates to a class of pyrimidine compounds whichare useful in the treatment of central nervous system (CNS) diseases anddisorders such as the prevention of cerebral ischaemic damage, topharmaceutical compositions containing them, to their use in thetreatment of such disorders, and to methods of preparing them.

Glutamate is an excitatory amino acid which functions as aneurotransmitter. However, when its extracellular concentration issufficiently high, glutamate acts as a powerful neurotoxin, capable ofkilling neurones in the central nervous system, (Rothman & Olney (1986)Prog. Brain. Res., 63, 69). The neurotoxic effect of glutamate has beenimplicated in a number of central nervous system disorders and diseasestates including cerebral ischaemic damage, epilepsy and chronicneurodegenerative disorders, such as Alzheimer's disease, motor systemdisorders, and Huntington's chorea, (Meldrum Clinical Science (1985) 68113-122). In addition, glutamate has been implicated in otherneurological disorders such as manic depression, depression,schizophrenia, high pressure neurological syndrome, chronic pain,trigeminal neuralgia and migraine.

In European Patent application No. 21121 there is disclosed a group of3,5-diamino-6-(substituted phenyl)-1,2,4-triazines which are active inthe treatment of CNS disorders, for example in the treatment ofepilepsy. One compound described in that application,3.5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (lamotrigine), hasbeen shown to inhibit the release of the excitatory amino acids,glutamate and aspartate, (Leach et al Epilepsia 27, 490-497 1986, A. A.Miller et al New anticonvulsant drugs. Ed. Meldrum and Porter 165-177,1987).

The present inventors have now found that a series of substitutedpyrimidine compounds, as defined in Formula I, are potent inhibitors ofglutamate release; these compounds are useful in the treatment of theabove mentioned disorders and disease states of the central nervoussystem. The pyrimidine compounds of formula I are also inhibitors ofaspartate release.

Thus in a first aspect of the present invention there is provided theuse of a compound of Formula I or an acid addition salt thereof in themanufacture of a medicament for treating or preventing CNS disorders ordiseases of a mammal, wherein ##STR1## in Formula I, R₁ and R₂ are thesame or different and are selected from hydrogen, halo, hydroxy, alkoxy,alkyl, alkylthio and a group NR¹ R¹¹ where R¹ and R¹¹ are the same ordifferent and are selected from hydrogen, alkyl, aryl and arylalkyl ortogether with the nitrogen atom to which they are attached form a cyclicring optionally substituted with one or more alkyl groups and optionallycontaining a further heteroatom;

R₃ is hydrogen, alkyl optionally substituted by one or more haloradicals, or is amino, alkylamino, dialkylamino, cyano, nitro, halo,carbamoyl, hydroxy, carboxy, alkoxy, alkylthio, alkylthioalkyl, S(O)_(n)alkyl, di(alkyloxy)alkyl, --C(R):NOH or --COR or --CO₂ R wherein R ishydrogen or alkyl, or a group CH₂ X where X is hydroxy, alkoxy, aryloxy,arylalkyloxy, halo, cyano, --NR¹ R¹¹ wherein R¹ and R¹¹ are as definedabove, S(O)_(n) -alkyl where n is 1 or 2, or SO₂ NR¹ R¹¹ ;

each of R₄ to R₈ are the same or different and each is selected fromhydrogen, halo, alkyl, perhaloalkyl, cyano, carbamoyl, carboxy, COR,nitro, amino, alkylsulphonylamino, alkoxy, S(O)_(n) -alkyl where n is 1or 2, or SO₂ NR¹ R¹¹ ; or

R₄ and R₅ or R₅ and R₆ together are the group --CH═CH--CH═CH-- or thegroup --CH₂ --CH₂ --CH₂ --CH₂ -- in which case both R₇ and R₈ arehydrogen; and optionally one of the nitrogen atoms in the pyrimidinering may be N alkylated or optionally may be an N oxide;

the foregoing alkyl groups or moieties of alkyl-containing groups havingfrom 1 to 6 carbon atoms, and the aryl groups or aryl moieties ofaryl-containing groups having 6 or 10 carbon atoms.

Certain compounds of Formula I are chiral, and it will be appreciatedthat in these instances, Formula I encompasses both the racemic mixtureand the individual enantiomers of such compounds. It will also beappreciated that when one or more of R₁, R₂ and R₃ are hydroxy, they mayalso exist in their tautomeric form.

A preferred class of compounds of Formula I which are potent inhibitorsof glutamate are those wherein one of R₁ and R₂ is amino and the otheris selected from amino, hydroxy, halo, morpholino, piperazinyl,N-alkylpiperazinyl, N,N-dialkylamino, N-alkylamino or alkylthio;

R₃ is alkyl optionally substituted by one or more halo radicals, or isalkyl, alkylthio, hydrogen, hydroxy, alkoxy, halo, carboxy, carbamoyl,or a group CH₂ X where X is hydroxy, phenoxy, benzyloxy, alkoxy oralkylthio;

one of R₄ and R₅ is halo and the other is selected from halo orhydrogen;

R₆ is halo, hydrogen, nitro or amino;

R₇ is hydrogen, halo, cyano, alkylthio, SO₂ NR¹ R¹¹ alkyl, nitro, aminoor methanesulphonamido; and

R₈ is hydrogen or halo.

In the present invention,

R₁ is preferably hydroxy, amino, N-alkylamino, N,N-dialkylamino,morpholino, piperazinyl, N-alkylpiperazinyl;

R₂ is preferably chloro, amino, N,N-dialkylamino or piperidino;

R₃ is preferably hydrogen, alkyl, methoxymethyl, trifluoromethyl,benzyloxymethyl, phenoxymethyl or methylthiomethyl;

R₄ to R₈ are preferably selected from hydrogen and chloro. Preferablythe alkyl moieties contain from 1 to 4 carbon atoms.

In Formula I, advantageously at least one of R₁ and R₂ is amino and theother is amino, piperazinyl or N-methylpiperazinyl, N-alkylamino,N,N-dialkylamino; and

R₃ is hydrogen, methyl, trifluoromethyl or methoxymethyl.

It is a preferred feature of Formula I that two of R₄, R₅ and R₇ arechloro, in particular it is preferred that all of R₄, R₅ and R₇ arechloro. Such compounds are highly potent inhibitors of glutamaterelease. Preferred examples of the group NR¹ R¹¹ are amino,N-methylamino, N-ethylamino, N,N-dimethylamino, piperazinyl,N-methylpiperazinyl, piperidinyl, and morpholino.

An especially preferred class of compounds within Formula I are thosewherein

R₁ is selected from amino, piperazinyl, N-methylpiperazinyl,N-morpholino, N,N-dimethylamino, and N-ethylamino;

R₂ is amino;

R₃ is selected from trifluoromethyl, hydrogen, methyl, benzyloxymethyl,methoxymethyl and methylthiomethyl;

R₄ is chloro; and

at least one of R₅, R₆ and R₇ is chloro, and the remainder are selectedfrom hydrogen, chloro and nitro; and

R₈ is hydrogen or R₄ and R₈ are both hydrogen, R₅ and R₇ are both chloroand R₆ is selected from hydrogen chloro and nitro.

The present invention also provides a subclass of compounds of FormulaI, which whilst being potent inhibitors of glutamate release show onlyweak (ie. having an IC₅₀ of >20 μm) or insignificant inhibitory effectson the enzyme dihydrofolate reductase. Accordingly, in a preferredembodiment of the present invention there is provided compounds ofFormula I where R₁ to R₈ are hereinbefore defined with the proviso thatwhen

R₇ is halo, then

R₃ is hydrogen, perhaloalkyl, methyl or methoxymethyl and/or

R₆ is nitro and/or

R₁ is N-alkylpiperazinyl, morpholino, N,N-dimethylamino, piperazinyl orN-ethylamino;

or with the proviso that when

R₆ is chloro then

R₄ is halo, and R₃ is hydrogen, perhaloalkyl, methoxymethyl, methyl orhalo and/or R₁ is N-methylpiperazinyl, piperazinyl, morpholino orN,N-dimethylamino, or N-ethylamino.

Compounds of Formula I may be used in the treatment or prophylaxis ofacute and chronic disorders of the mammalian central nervous system. Theacute condition comprises cerebral ischaemia which may arise from avariety of causes including stroke, cardiac arrest, bypass surgery,neonatal anoxia and hypoglycaemia; and also physical injury or trauma ofthe spinal cord or brain. Chronic neuro- degenerative disorders whichmay be treated include Alzeheimer's disease, Huntington's chorea,Olivopontocerebrellar atrophy, motor system disorders. Otherneurological conditions which may be treated with a compound of FormulaI include depression, manic depression, schizophrenia, chronic pain,epilepsy, trigeminal neuralgia and migraine.

In a further aspect, the present invent ion provides a method oftreatment or prevention of a CNS disorder or disease of a mammal,including man, comprising the administration to the mammal of anon-toxic effective amount of a compound of Formula I or an acidaddition salt thereof.

In particular, the present invention provides a method of treating amammal predisposed to or having neurotoxic extracellular glutamatelevels of the central nervous system comprising the administration tothe mammal of a non-toxic effective amount of a compound of Formula I oran acid addition salt thereof.

Certain substituted phenylpyrimidines of the present invention are knownin the art as having antimalarial activity. See for example Brit. J.Pharmacol. 6, 185-200 (1951); JACS, 73, 3763-70, (1951). Otherphenylpyrimidines are known from Chem. Biol. Pteridines, 463-468, (1982)and Pharmacotherap. Budesinsky, p. 129-141, (1963), ed. Oldrich Hanc.

Nonetheless, certain compounds of the present invention are novel andaccordingly the present invention provides a compound of Formula I or anacid addition salt thereof wherein R₁ to R₈ are as hereindefined, withthe proviso that at least one of R₄ to R₈ is other than hydrogen, andfurther with the proviso that when R₁ and R₂ are both amino, or when R₁is hydroxy and R₂ is amino, and R₃ is alkyl or hydrogen, and R₇ ishydrogen, then R₄ and R₅ are both halo.

Other novel compounds of the present invention are those where R₁ to R₃and R₈ are as hereinbefore defined and one of R₄ or R₅ is other thanhydrogen, and R₇ is halo, alkyl, perhaloalkyl, cyano, nitro, amino,alkylthio, S(O)_(n) -alkyl or SO₂ NR¹ R¹¹.

A third class of novel compounds of the present invention are those ofFormula I where R₁ is morpholino, piperazinyl, N-alkylpiperazinyl,N,N-dialkylamino, N-alkylamino or alkylthio and R₂ to R₈ are ashereinbefore defined.

A fourth class of novel compounds of the present invention are those ofFormula I where R₁ and R₂ are as hereinbefore defined;

and R₃ is alkoxy, alkylthio or alkyl substituted by one or more haloradicals, or is a group CH₂ X where X is alkylthio, aryloxy,arylalkyloxy, alkyloxy or hydroxy;

R₄ to R₆ are the same or different and are each selected from hydrogen,halo, perhaloalkyl, cyano, nitro, amino or alkylthio;

R₇ is halo, alkyl, perhaloalkyl, cyano, nitro, amino, or a group SO₂N(R¹¹¹)₂ wherein R¹¹¹ is alkyl; and

R₈ is hydrogen or halo.

A fifth class of novel compounds of the present invention are those ofFormula I where R₁ and R₂ and R₄ to R₈ are as hereindefined, and R₃ isalkoxy, aryloxy, arylalkyloxy or alkylthio.

Preferred novel compounds of the present invention include thefollowing, the numbers referring to the Examples hereinafter appearing:

EXAMPLE NO.

1.4-Amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine

2. 2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-methoxymethylpyrimidine

3.4-Amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine

4. 2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine

5. 2,4-Diamino-5-(4-nitro-2,3,5-trichlorophenyl)pyrimidine

6. 2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-methylpyrimidine

7.4-Amino-2-N-morpholino-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine

8.4-Amino-2-N,N-dimethylamino-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine

9. 4-Amino-2-morpholino-N-5-(2,3,5-trichlorophenyl)pyrimidine

10. 4-Amino-2-N,N-dimethylamino-5-(2,3,5-trichlorophenyl)pyrimidine

11.4-Amino-6-methyl-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine

14. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-trifluoromethylpyrimidine

15. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-methylpyrimidine

16. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-methoxymethylpyrimidine

25. 2,4-Diamino-5-(2,4-dichlorophenyl)-6-trifluoromethylpyrimidine

26. 6-Benzyloxymethyl-2,4-diamino-5-(2,4-dichlorophenyl)pyrimidine

27. 2-N-methylpiperazinyl-4-amino-5-(2,4-dichlorophenyl)pyrimidine

28. 2,4-Diamino-5-(2,5-dichlorophenyl)-6-trifluoromethylpyrimidine

29. 2,4-Diamino-5-(2,3,5-trichlorophenyl)pyrimidine

36.4-Amino-5-(3,5-dichlorophenyl)-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidine

58. 4-Amino-2-N-ethylamino-5-(2,3,5-trichlorophenyl)pyrimidine

79. 4-Amino-2-N-methylamino-5-(2,3,5-trichlorophenyl)pyrimidine

or an acid-addition salt thereof.

Suitable acid addition salts of the compounds of Formula I include thoseformed with both organic or inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. Thus, preferred saltsinclude those formed from hydrochloric, hydrobromic, sulphuric, citric,tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic,fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic,p-toluenesulphonic, benzenesulphonic and isethionic acids. These saltscan be made by reacting the compound as the free base with theappropriate acid.

While it is possible for the compounds of Formula I to be administeredas the raw chemical, it is preferable to present them as apharmaceutical formulation. The formulations of the present inventioncomprise a novel compound of Formula I, as above defined, or apharmaceutically acceptable salt thereof together with one or moreacceptable carriers therefor and optionally other therapeuticingredients. The carrier(s) must be `acceptable` in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing into association a compound of Formula I or apharmaceutically acceptable acid addition salt thereof ("activeingredient") with the carrier which constitutes one or more accessoryingredients. In general the formulations are prepared by uniformly andintimately bringing into association the active ingredient with liquidcarriers or finely divided solid carriers or both and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain antioxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example, water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose and acacia.

Preferred unit dosage formulations are those containing an effectivedose, an hereinbelow recited, or an appropriate fraction thereof, of theactive ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

Tablets or other forms of presentation provided in discrete units mayconveniently contain an amount of compound of the Formula I which iseffective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 250 mg.

The compounds of the Formula I are preferably used to treat CNSdisorders or diseases by oral administration or injection(intraparenteral or subcutaneous). The precise amount of compoundadministered to a patient will be the responsibility of the attendantphysician. However the dose employed will depend on a number of factors,including the age and sex of the patient, the precise disorder beingtreated, and its severity. Thus for example when treating a patient withepilepsy the dose range is likely to be significantly lower than whentreating a patient after stroke to allevieate cerebral ischaemic damage.Also the route of administration is likely to vary depending on thecondition and its severity.

The compounds of the Formula I may be administered orrally or viainjection at a dose of from 0.1 to 30 mg/kg of mammal, e.g., humanbodyweight per day more preferably 2 to 15 mg/kg of mammal, e.g., humanbodyweight for each of the indications (disorders or diseases)previously indicated above, e.g., epilepsy and cerebral ischaemic damageafter stroke. The dose range for adult humans is generally from 8 to2,400 mg/day and preferably 35 to 1,050 mg/day. As certain compounds ofthe Formula I are long acting, it may be advantageous to administer aninitial dose of 70 to 2,400 mg the first day then a lower dose of 20 to1,200 mg on subsequent days. If the salt of the compound is administeredin place of the compound, then the amount of salt administered iscalculated in terms of the base.

Examples of such long acting compounds are:

2,4-diamino-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine;4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine;and

4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine.

Long acting compounds in the clinic are advantageous because they areeasier to manage. In the chronic situation, they may be administeredwithout infusion and there is the minimum of direct medicalintervention; also in acute conditions, patient compliance is encourageby minimising daily dosing. Conversely, short acting compounds such as:

2,4-diamino-5-(2,3,5-trichlorophenyl)-6-methoxymethylpyrimidine

permit the clinician to control the pharmacological effect of thecompound with great precision, since such compounds will be cleared fromthe central nervous system rapidly.

Compounds of the present invention may be made in any manner known tomake analogous compounds known in the art (eg. JACS vol 73 (1951)3763-70).

The present invention also provides a process for the preparation of acompound of Formula I or an acid addition salt thereof, which comprisesthe reaction of a compound of Formula II ##STR2## wherein R₃ to R₈ areas hereinbefore defined, L is a leaving group, and Y is cyano orcarboxy, carbonyl, or alkoxycarbonyl with a compound or salt thereof offormula III ##STR3## wherein R₁ is as hereindefined, and isolating thecompound of Formula I as the free base or an acid addition salt thereof,and optionally converting the base into an acid addition salt thereof orinto another acid addition salt, or into another compound of Formula Ior an acid addition salt thereof.

It will be appreciated that certain compounds of Formula III for examplewhere R₁ is hydroxy exists in the corresponding tautomeric form (eg. asurea).

As examples of interconversion of compounds of Formula I, when in theproduct of the above process one of R₁, R₂ or R₃ is hydroxy the compoundmay be halogenated for example using the Vilsmeier Haack reagent orphosphorus oxychloride (POCl₃), to the corresponding halo compound. Thiscompound may be further converted into a compound of Formula I whereinR₁, R₂ or R₃ is alkylthio by reaction with the appropriate alkylthiolateor to the corresponding amino compound (R₁, R₂ or R₃ being NR¹ R¹¹) byreaction with the appropriate amino compound in a suitable solvent suchas an alkanol, e.g. ethanol, or converted to a compound where R₁, R₂ orR₃ is alkoxy by reaction with appropriate alkoxide.

If it is required to make a compound of Formula I in which one of R₄ toR₈ is nitro, this can be made from the corresponding compound of FormulaI where one of R₄ to R₈ is hydrogen by utilising standard nitrationconditions, e.g. sulphuric acid and potassium nitrate, and then furtherconverted by standard reduction means to the corresponding aminocompound, e.g. utilising PtO₂, AcOH, H₂.

It will be appreciated that amino or halo compounds can be furtherconverted to R₄ to R₈ as herewithin defined by standard interconversion,for example, via the diazonium salts. When R₃ is alkyl this may beconverted into perhaloalkyl, or a halogenated alkyl moiety by reactionwith the appropriate halogen or N-halo succinimide (NXS) in a suitablesolvent such as acetic acid.

Compounds in which R₃ is CH(OEt)₂ may be converted into thecorresponding aldehyde by hydrolysis with dilute acid(s) and thereafterreduced to the corresponding alcohol with a standard reducing agent(e.g. sodium borahydride NaBH₄), or converted to the corresponding oxime(hydroxylamine hydrochloride in ethanol), which in turn can be convertedto the corresponding cyano compound utilising, for exampletrifluoroacetic anhydride (TFAA), and then to the corresponding amidocompound utilising concentrated sulphuric acid. Alternatively, thealdehyde may be oxidised with KMnO₄ (potassium permanganate) to give thecorresponding acid, which may in turn be reacted with an alcohol to givethe corresponding ester.

Where in the product of the above process R₃ is a group CH₂ OR where Ris alkyl or arylalkyl this product may be converted to CH₂ X by reactionwith HX (X=halo) in, for example acetic acid, and this further convertedto the corresponding cyano compound, for example by treatment withsodium cyanide and DMF, or to fluoromethyl by treatment with for examplecesium fluoride (CsF) or to a group CH₂ NR¹ R¹¹ by reaction with theappropriate amine. Alternatively, the group CH₂ OR can be dealkylated togive the corresponding alcohol, for example with Me₃ SiI, and thisfurther converted to fluoromethyl with diethylaminosulphur trifluoride(DAST).

Where R₃ to R₈ contains an alkylthio moiety, this can be oxidised to thecorresponding sulphoxide and sulphone using for example MCPBA(metachloroperbenzoic acid).

It will be appreciated that other interconversions may be effected asrequired by those skilled in the art using standard methodologies.

Examples of suitable leaving groups (L) include C₁₋₄ alkoxy, halo, NR¹R¹¹ as hereindefined e.g. anilino, morpholino, C₁₋₄ alkylamino,benzylamino, or alkylthio. Preferably in Formula III, R₁ is hydroxy,alkoxy, alkylthio, or a group NR¹ R¹¹ as herein defined. AdvantageouslyR₁ is amino, alkylamino, dialkylamino, piperazinyl orN-methylpiperazinyl.

Preferably the reaction of the compound of Formula I and II is carriedout in a non-aqueous solvent, for example an alkanol, e.g. ethanol atelevated temperatures (e.g. between 50° to 110° C.) in a base,preferably an alkanoxide, preferably under reflux using sodium ethoxideas the base.

Alternatively a compound of Formula I or an acid addition salt thereofmay also be made by the reaction of a compound of Formula III with acompound of Formula IV ##STR4## wherein R₃ to R₈ and Y are as hereindefined. The reaction preferably takes place in a non-aqueous solvent,e.g. alkanols, such as ethanol, and at elevated temperatures, preferablyunder reflux.

Compounds of formula IV can be made by methods known in the art (JACS,1951, 73, 3763-3770).

Compounds of Formula II may be made by methods known in the art (JACSsupra) for example by the reaction of a compound of Formula IV withdiazomethane or with alkylorthoesters (JACS, 1952, 74, 1310-1313), or bycondensation with an amine.

In Formula III when R¹ is piperazinyl or alkyl piperazinyl these can bemade by standard methods for example by reaction of a known compound ofFormula III where R¹ is alkylthio with the appropriate amine, e.g.N-methylpiperazine. This reaction preferably takes place at roomtemperature in water.

Compounds of formula I may also be made by the reaction of a compound ofFormula V ##STR5## wherein Y and R₃ are as hereinbefore defined and R₁₀and R₁₁ are alkyl or collectively form a group (CR₂)_(n) where n is 2 to4 and R is H or alkyl, with a compound of Formula III. Most preferablyR₁ is amino, piperazinyl or methyl piperazinyl. Preferably the reactionis carried out in a non-aqueous solvent, e.g. ethanol, under refluxusing sodium ethoxide as the base.

Compounds of Formula I may also be prepared from the correspondingdihydropyrimidine by utilising standard dehydrogenation conditions,(e.g. JCS, 1956, 1019).

Such dihydropyrimidine can be prepared by the reaction of a compound ofFormula II where R₃ to R₈ are as defined and L is hydrogen with acompound of Formula III.

In the Examples of the invention set forth below, the chemical and otherabbreviations used are standard in the art and have these meanings:

    ______________________________________    NaBH.sub.4   sodium borohydride    CHCl.sub.3   chloroform    NaHCO.sub.3  sodium bicarbonate    MgSO.sub.4   magnesium sulphate    PBr.sub.3    phosphorus tribromide    DMF          dimethylformamide    KCN          potassium cyanide    Et.sub.2 O   diethyl ether    NaOEt        sodium ethoxide    EtOH         ethanol    H.sub.2 SO.sub.4                 sulphuric acid    AcOH         acetic acid    MeOH         methanol    N.sub.2      nitrogen    HCl          hydrochloric acid    NaOH         sodium hydroxide    SiO.sub.2    silica    DMSO         dimethylsulphoxide    Na           sodium    DME          dimethoxyethane    MeI          methyl iodide (iodomethane)    EtOAc        ethyl acetate    CH.sub.2 Cl.sub.2                 dichloromethane    Et.sub.3 N   triethylamine    MeNH.sub.2   methylamine    NH.sub.4 OH  ammonium hydroxide    SOCl.sub.2   thionyl chloride    THF          tetrahydrofuran    NaH          sodium hydride    CCl.sub.4    carbon tetrachloride    DHFR         dihydrofolate reductase    PtO.sub.2    platinum oxide (Adams' catalyst)    NXS          N-halo succinimide    X.sub.2      halogen    TFAA         trifluoroacetic anhydride    CsF          cesium fluoride    Me.sub.3 SiI trimethylsilyliodide    DAST         diethylaminosulphur trifluoride    MCPBA        metachloroperbenzoic acid    AIBN         a,a'-azoisobutyronitrile                 (2,2'-azobis(2-methylpropionitrile)    ______________________________________

EXAMPLE 1 Preparation of4-Amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-tricholrophenyl)-6-trifluoromethylpyrimidine

1. Preparation of N-methylpiperazinoformamidine hydriodide

Thiourea (10.8 g) was dissolved in acetone (250 ml) at 50° C.Iodomethane (10 ml) was added and the reaction was stirred at 50° C. for4 hours. After cooling, the solution was diluted with ether (1 liter)and the methiodide salt was filtered, washed with ether and dried invacuo, 29.2 g 113°-115° C. The methiodide'salt (5 g) was dissolved inwater, (30 ml) and N-methylpiperazine was added. The solution wasstirred, with nitrogen bubbled through, at room temperature for 24hours. The solution was concentrated in vacuo. The residue was slurriedwith ethanol, filtered and dried in vacuo, 4.98 g, m.pt. 230°-242° C.

2. Preparation of 2,3,5-trichlorobenzylalcohol

To a solution of 2,3,5-trichlorobenzaldehyde (Aldrich, 50 gms) inethanol (1.0 L) at room temperature was added NaBH₄ (7.00 gms) and theresulting mixture stirred for 3.5 hours. The reaction was quenched withwater, and the solvent evaporated in vacuo before partitioning theresidue between CHCl₃ and saturated NaHCO₃ solution. The organic phasewas washed with brine, dried over MgSO₄, filtered and the solventevaporated in vacuo to leave a white solid. 43.00 gms, mp. 90°-93° C.

3. Preparation of 2,3,5-trichlorobenzyl bromide

To a solution of the alcohol in benzene (400 ml) under N₂ was added PBr₃(126.58 gms), and the mixture stirred at 55°-60° C. for 3.5 hours. Aftercooling, the mixture was poured onto crushed ice (2 L) and the benzenelayer separated. The aqueous phase was washed with benzene (×3) and thecombined benzene extracts washed with saturated NaHCO₃ solution andwater, dried over MgSO₄, filtered and the solvent evaporated to leave abrownish liquid which solidified on standing, 37.53 gms, mp. 40°-42° C.

4. Preparation of 2,3,5-trichlorophenylacetonitrile

The bromide was suspended in DMF (130 ml)/water(86.67 ml) at 0° C. andKCN(12.99 gms) added in portions. After stirring at 30°-35° for 3 hours,the suspension was diluted with water and extracted with Et₂ O. Thecombined ether extracts were washed with water, dried over MgSO₄,filtered and the solvent evaporated in vacuo. Chromatography on silicagel eluting with hexane to 20% ether-hexane gave the desired product asa white solid, 18.52 gms, mp. 60°-62° C.

5. Preparation of2-(2,3,5-trichlorophenyl)-4,4,4-trifluoro-3-oxo-butyronitrile

To a solution of NaOEt (from 1.04 gms Na) in EtOH (60 ml) at roomtemperature under N₂ was added the nitrile (8.40 gms) followed by ethyltrifluoroacetate (6.57 gms) and the mixture stirred at reflux for 5hours. After cooling, the solvent was removed in vacuo and the residuedissolved in water. The aqueous phase was washed with Et₂ O (discarded),acidified with H₂ SO₄ and extracted with Et₂ O. The combined Et₂ Oextracts were washed with water, dried over MgSO₄, filtered and thesolvent evaporated in vacuo to leave an oil. This was triturated withpetroleum ether, and the solid filtered off and dried. The solid wasazeotroped with toluene (×5), 4.89 gms, mp. 160°-163° C.

6. Preparation of2-(2,3,5-trichlorophenyl)-4,4,4-trifluoro-3-methoxybut-2-enonitrile

To a solution of the trifluoromethyl ketone in Et₂ O (39.62 ml) at roomtemperature was added diazomethane (from 8.55 gms Diazald) in Et₂ O(79.62 ml), and the resulting mixture left to stand at room temperatureovernight. Excess diazomethane was then removed in vacuo into AcOH, andthe residue was dissolved in Et₂ O, dried over MgSO₄, filtered and thesolvent evaporated in vacuo to leave a brownish oil, 5.20 gms.

7. Preparation of4-Amino-2-(4-methylpiperazinyl-yl)-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine

To a solution of NaOEt (from 0.144 g of Na) in EtOH (12.5 ml) was addedN-methylpiperazinoformamidine hydriodide (1.39 g). After stirring for 10minutes at room temperature a solution of the above intermediate (0.85g) in EtOH (2.5 ml) was added and the resulting mixture was stirred atreflux for 4.5 hours. After cooling, the suspension was filtered, andthe filtrate was evaporated to dryness in vacuo. Chromatography onsilica gel, eluting with CHCl₃ -4% MeOH/CHCl₃, gave the desired productwhich was triturated with petroleum ether (b.p. 40°-60° C.) and dried invacuo. 0.56 g, m. pt 127°-129° C.

8.4-Amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidinemethanesulphonate

The phenyl pyrimidine base (9.6 g) was dissolved in absolute ethanol,cooled at 0° C., and methanesulphonic acid (2.14 g, 1.62 ml) was added.After stirring at room temperature for 2 hours, the solution wasevaporated to dryness and the residue triturated with Et₂ O, filteredand dried in vacuo to leave a beige coloured solid. This was dissolvedin water (500 mls) and freeze-dried to leave 10.7 g as a tan colouredsolid. The methanesulphonate salt could be further purified bytriturating with ^(t) BuOH (30 ml), filtering, dissolving in water andagain freeze drying to leave the title product as a off-white solid.8.33 g mp. 145°-7° C.

EXAMPLE 2 Preparation of2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-methoxymethyl pyrimidine

A. 2-(2,3,5-trichlorophenyl)-4-methoxy-3-oxo-butyronitrile

To a stirred refluxing solution of sodium ethoxide (from 1.38 g sodium)in ethanol (25 ml) was added over 5 minutes a mixture of2,3,5-trichlorophenylacetonitrile (11 g) and ethyl methoxyacetate (8.85g) in dry DME (25 ml). After 4 hours the mixture was cooled on ice andacidified by dropwise addition of acetic acid (ca. 6 ml), diluted withice-water (10 ml) and extracted with dichloromethane (2×100 ml). Thedichloromethane extract was washed with water, dried over MgSO₄ andconcentrated giving a yellow solid, which was triturated with a littleether and filtered. 8.6 g Homogeneous by TLC (19:1 CH₂ Cl₂ :MeOH).

B. Preparation of2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-methoxymethylpyrimidine

A suspension of the crude acyl acetonitrile (8.5 g) in ether (100 ml),cooled on ice was treated with an excess of an alcohol free solution ofdiazomethane in ether (0.035M). After one hour TLC (19:1 CH₂ Cl₂ :MeOH)showed no starting material. The solution was concentrated to give abrown waxy solid, which was used without further purification.

To a solution of sodium ethoxide (from 0.76 g sodium) in ethanol (30 ml)was added guanidine hydrochloride (2.9 g). After 15 minutes a solutionof the crude enol ether in ethanol (25 ml) was added and the mixturerefluxed with stirring for 4 hours, cooled and concentrated. The residuewas shaken with 2M NaOH (150 ml) and the dark solid filtered off, washedwith water, dried in air and recrystallised from ethanol (150 ml).

5 g M.pt. 214°-216° C. TLC (1:9 MeOH:CHCl₃) Rf.sup.˜ 0.35.

C. 2,4-Diamino-5-(2,3,5,-trichlorophenyl)-6-methoxymethylpyrimidineethanesulphate

To a stirred suspension of the phenylpyrimidine (2 g) in ethanol (75 ml)was added dropwise ethanesulphonic acid (0.67 g) in ethanol (10 ml).After ca 30 minutes the solution became cloudy. Stirring was continuedfor a further 1.5 hours and the solvent then concentrated to ca 20 mls.Ether was added, the solid filtered off and washed with Et₂ O beforedrying in vacuo, 2.17 g, m.pt. 265°-268° C.

EXAMPLE 3 Synthesis of4-Amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidinemesylate

1. preparation of 2-(2,3,5-trichlorophenyl)-3-oxo-propionitrile, sodiumsalt

To a solution of NaOEt (from 0.803 g of sodium) in ethanel (55 ml)cooled in ice, under nitrogen, was added 2,3,5-trichlorophenylacetonitrile (see Example 1.4). Ethyl formate (5.1 ml) was added and themixture was stirred at room temperature overnight. After stirring for afurther 2.5 hours at 50° C., the mixture was cooled and filtered. Thefiltrate was evaporated, and the residue was triturated with diethylether, filtered and dried (6.82 g).

2. Preparation of 2-(2,3,5-trichlorophenyl)-3-methoxy-acrylonitrile

The above solid was dissolved in DMF (36 ml) and methyl iodide (2 ml)was added. The reaction vessel was sealed before stirring the contentsat 40° C. for 3 hours. The solvent was then evaporated. The residue waspartitioned between water and ethyl acetate. The organic phase waswashed with water, dried (MgSO₄) and the solvent evaporated to give thecrude product as a red-brown oil that solidified on standing (5.04 g).

3. Preparation of4-Amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine

To a solution of NaOEt (from 0.21 g of sodium) in ethanol (20 ml) wasadded N-methylpiperazinoformamidine hydriodide (2.06 g) (see Example1.1). After stirring for a further 10 minutes, the compound of Example3.2 (1 g) was added and the mixture was stirred at reflux for 4 hours.The mixture was left standing at room temperature overnight and thenfiltered. The filtrate was concentrated and the residue was purified bychromatography on SiO₂, eluting with CHCl₃ to 4% MeOH/CHCl₃ to give thetitle compound as the free base. 0.89 g, mp. 162°-164° C.

The free base (0.805 g) was then dissolved in ethanol (35 ml) and cooledin an ice bath. Methanesulphonic acid (0.21 g) was added and thereaction was stirred at room temperature for 2 hours. The solvent wasthen evaporated and the residue was triturated with diethyl ether,filtered, dissolved in cold water and freeze dried to give the titlesalt as a pale green solid, 0.98 g, mp. 143°-146° C.

EXAMPLE 4 Synthesis of2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-trifluoromethyl pyrimidine

To a solution of NaOEt (from 0.88 g of Na) in EtOH (82 ml) was addedguanidine hydrochloride (2.98 g). The resulting white suspension wasstirred at room-temperature for 10 minutes. A solution of the enol ether(Example 1.6) in ethanol (27 ml) was added and the resulting mixturestirred at reflux for 4.25 hours. After cooling, the suspension wasfiltered, and the filtrate evaporated to dryness in vacuo.Chromatography on silica gel eluting with CHCl₃ to 2% MeOH:CHCl₃ gavethe desired product which was triturated with Et₂ O and dried in vacuo,1.78 gms, m.p. 226°-227° C.

EXAMPLE 5 Preparation of2,4-Diamino-5-(4-nitro-2,3,5-trichlorophenyl)pyrimidine

The compound from Example 29 was dissolved in concentrated sulphuricacid (2.5 ml), potassium nitrate (25.8 mg) added and the solutionstirred for 3 hours. The solution was then poured onto ice and basifiedwith 10N NaOH. The product was extracted with ethyl acetate (×3), driedover MgSO₄, filtered and the solvent evaporated. Chromatography onsilica gel eluting with ethyl acetate gave the desired product, 40.7 mg,mp. 293°-295° C.

EXAMPLE 6 Preparation of 2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-methylpyrimidine

1. Preparation of 2-(2,3,5-trichlorophenyl)-3-oxobutyronitrile

To a solution of NaOEt (from 0.68 g of sodium) in ethanol (20 ml) wasadded 2,3,5-trichlorophenylacetonitrile (5 g) and ethyl acetate (4.43ml). The mixture was heated under reflux, under nitrogen for 2.5 hours.The mixture was left standing at room temperature overnight. The mixturewas then concentrated and the residue was dissolved in water. Theaqueous phase was washed with ether, acidified with concentrated H₂ SO₄and extracted with ether. The extracts were bulked, dried (MgSO₄) andevaporated, 2.59 g, mp. 134°-135° C.

2, preparation of 2-(2,3,5-trichlorophenyl)-3-methoxybut-2-enonitrile

To a solution of the ketone in ether (100 ml) at room temperature wasadded diazomethane (from 5.43 g Diazald (in ether (50 ml) and theresulting mixture was left to stand at room temperature overnight. Theether was then distilled off to leave the desired product 2.45 g.

3. Preparation of2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-methylpyrimidine

Guanidine hydrochloride (3.87 g) was added to a solution of sodiumethoxide (from 1.01 g of sodium) in ethanol (80 ml). The resulting whitesuspension was stirred at room temperature for 10 minutes and then addedto a solution of the enol ether (Example 6.2) (5.60 g) in ethanol (20ml). The resulting mixture was stirred at reflux for 8 hours undernitrogen. After cooling, the suspension was filtered, and the filtrateevaporated to dryness in vacuo. Chromatography on silica gel elutingwith CHCl₃ to 2% MeOH--CHCl₃ gave the desired product which wastriturated with ether and dried in vacuo. Yield 1.70 g, mp. 236°-238° C.

EXAMPLE 7 Preparation of4-Amino-2-N-morpholino-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine.

To a solution of NaOEt (from 0.144 g of Na) in EtOH (12.5 ml) was addedmorpholinoformamidine hydrobromide (1.08 g) (Lancaster Synthesis). Theresulting white suspension was stirred at room temperature for 10minutes. A solution of the enol ether (0.85 g) (Example 1.6) in EtOH(2.5 ml) was added and the resulting mixture was stirred at reflux for4.5 hours. After cooling, the suspension was filtered, and the filtratewas evaporated to dryness in vacuo. Chromatography on silica gel,eluting with CHCl₃, gave the desired product which was triturated withpetroleum ether (b.p. 40°-60° C.) and dried in vacuo, 0.47 g, mp.177°-181° C.

EXAMPLE 8 Preparation of4-Amino-2(-N,N-dimethylamino)-5-(2,3,5-trichlorophenyl)-6-trifluoromethylpyrimidine.

To a solution of NaOEt (from 0.144 g of Na) in EtOH (12.5 ml) was added1,1-dimethylguanidine sulphate (1.4 g), (Aldrich). The resulting whitesuspension was stirred at room temperature for 10 minutes. A solution of2-(2,3,5-trichlorophenyl)-4,4,4-trifluoro-3-methoxybut-2-enonitrile (seeExample 1.6) (0.85 g) in EtOH (2.5 ml) was added and the resultingmixture was stirred at reflux for 4.5 hours. After cooling, thesuspension was filtered, and the filtrate was evaporated to dryness invacuo. Chromatography on silica gel, eluting with CHCl₃, gave thedesired product, 0.61 g, mp. 124°-126° C.

EXAMPLE 9 Synthesis of4-Amino-2-N-morpholino-5-(2,3,5-trichlorophenyl)pyrimidine

To a solution of NaOEt (from 0.21 g of sodium) in ethanol (20 ml) wasadded morpholinoformamidine hydrobromide (1.6 g). After stirring for 10minutes the adduct of Example 3.2 (1 g) was added and the mixture wasstirred at reflux for 4 hours. The mixture was left standing at roomtemperature overnight and then filtered. The filtrate was concentratedand the residue was purified by chromatography on SiO₂ gel, eluting withCHCl₃ to give the desired product, 0.73 g, mp. 168°-170° C.

EXAMPLE 10 Synthesis of4-Amino-2-(N,N-dimethylamino)-5-(2,3,5-trichlorophenyl)pyrimidine

To a solution of NaOEt (from 0.21 g of sodium) in ethanol (20 ml) wasadded 1,1-dimethylguanidine sulphate (2.07 g). After stirring for 10minutes the adduct of Example 3.2 (1 g) was added and the mixture wasstirred at reflux for 4 hours. The mixture was left standing at roomtemperature overnight and then filtered. The filtrate was concentratedand the residue was purified by chromatography on SiO₂, eluting withCHCl₃ to give the desired product, 0.69 g, mp. 145°-147° C.

EXAMPLE 11 Synthesis of4-Amino-6-methyl-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine

To a solution of NaOEt (from 0.16 g of sodium) in ethanol (15 ml) wasadded N-methylpiperazinoformamidine hydriodide (1.6 g). After stirringfor 10 minutes the enol ether of Example 6.2 (0.82 g) in ethanol (5 ml)was added and the mixture was stirred at reflux for 5 hours. The mixturewas left standing at room temperature overnight and then filtered. Thefiltrate was concentrated and the residue was purified by chromatographyon SiO₂ gel, eluting with CHCl₃ to 4% MeOH/CHCl₃ to give the desiredproduct, 0.31 g, mp. 156°-159° C.

EXAMPLE 12 Synthesis of2,4-diamino-6methyl-5-(2,3,5-trichloro-4-nitrophenyl)pyrimidine

2,4-Diamino-6-methyl-5-(2,3,5-trichlorophenyl)pyrimidine (0.152 g)(Example 6) was dissolved in concentrated sulphuric acid and potassiumnitrate (50 mg) was added. The solution was stirred at room temperatureovernight, then poured onto ice and basified with 0.880 ammonia. Theproduct was extracted into ethyl acetate, bulked, dried (MgSO₄) andevaporated. The residue was purified by chromatography on SiO₂ gel,eluting with EtOAc to 8% MeOH/EtOAc to give the desired product, 0.13 g,mp. 313°-315° C.

EXAMPLE 13 Synthesis of4-Amino-2-(N,N-dimethylamino)-6-methyl-5-(2,3,5-trichlorophenyl)pyrimidine

To a solution of NaOEt (from 0.16 g of sodium) in ethanol (15 ml (wasadded 1,1-dimethylguanidine sulphate (1.6 g). After stirring for 10minutes the enol ether of Example 6.2 (0.82 g) in ethanol (5 ml) wasadded and the mixture was stirred at reflux for 5 hours. The mixture wasleft standing at room temperature overnight and then filtered. Thefiltrate was concentrated and the residue was purified by chromatographyon SiO₂ gel, eluting with CHCl₃ to give the desired product, 54 mg, mp.151°≧153° C.

EXAMPLE 14 Synthesis of2,4-Diamino-5-(2,3-dichlorophenyl)-6-trifluoromethyl pyrimidine

1. Preparation of 2,3-dichlorobenzyl alcohol

To a solution of 2,3-dichlorobenzaldehyde (Aldrich, 50 gms) in alcohol(800 mL) at room temperature was added NaBH₄ (8.54 gms) and theresulting mixture stirred for 1.5 hours. The reaction was quenched withwater and the solvent evaporated in vacuo before partitioning theresidue between CHCl₃ and saturated NaHCO₃ solution. The organic phasewas washed with brine, dried over MgSO₄, filtered and the solventevaporated in vacuo to leave a white solid, 48.38 gms, mp. 87°-87.5° C.

2. Preparation of 2,3-dichlorobenzyl bromide

To a solution of the alcohol in benzene (500 ml) under N₂ was added PBr₃(167.8 gms), and the mixture stirred at 55°-60° C. for 3.5 hours. Aftercooling, the mixture was poured onto crushed ice (2 L) and the benzenelayer separated. The aqueous phase was washed with benzene (×3) and thecombined benzene extracts washed with saturated NaHCO₃ solution andwater, dried over MgSO₄, filtered and the solvent evaporated to leave abrownish liquid which solidified on standing. 37.53 gms, mp. 31°-32° C.

3. Preparation of 2,3-dichlorophenylacetonitrile

The bromide was suspended in DMSO (155 ml)/ water(105 ml) at 0° C. andKCN (20.24 gms) added in portions. After stirring at 30°-35° C. for 2hours, the suspension was diluted with water and extracted with Et₂ O.The combined ether extracts were washed with water, dried over MgSO₄,filtered and the solvent evaporated in vacuo to leave a white solid,27.52 gms, mp. 64°-67° C.

4. Preparation of2-(2,3-dichlorophenyl)-4,4,4-trifluoro-3-oxobutyronitrile

To a solution of NaOEt (from 1.48 gms Na) in EtOH (25 ml) at roomtemperature under N₂ was added the nitrile (10.0 gms) followed by ethyltrifluoroacetate (9.3 gms) and the mixture stirred at reflux for 5hours. After cooling, the solvent was removed in vacuo and the residuedissolved in water. The aqueous phase was washed with Et₂ O (discarded),acidified with H₂ SO₄ and extracted with Et₂ O. The combined Et₂ Oextracts were washed with water, dried over MgSO₄, filtered and thesolvent evaporated in vacuo to leave an oil. This was triturated withpetroleum ether, and the solid filtered off and dried. 9.56 gms, mp.74°-75° C.

5. Preparation of2-(2,3dichlorophenyl)-4,4,4-trifluoro-3-methoxybut-2-enonitrile

To a solution of the trifluoromethyl ketone in Et₂ O (90 ml) at roomtemperature was added diazomethane (from 19.35 gms Diazald) in Et₂ O(180 ml), and the resulting mixture left to stand at room temperatureovernight. Excess diazomethane was then removed in vacuo into AcOH, andthe residue was dissolved in Et₂ O, dried over MgSO₄, filtered and thesolvent evaporated in vacuo to leave a brownish solid, 6.44 gms.

6. Preparation of 2,4-Diamino-5-(2,3-dichlorophenyl)-6-trifluoromethylpyrimidine

To a solution of the above enol ether in ethanol (37 ml) was addedguanidine hydrochloride (1.92 gms) followed by a solution of NaOEt (from540 mgs of Na) in EtOH (90 ml), and the resulting mixture stirred atreflux for 3 hours. After cooling, the suspension was filtered, and thefiltrate evaporated to dryness in vacuo. Chromatography on silica geleluting with CHCl₃ to 2% MeOH-CHCl₃ gave the desired product which wastriturated with Et₂ O and dried in vacuo, 673 mg, m.pt. 218°-9° C.

7. 2,4-Diamino-5-(2,3dichlorophenyl)-6-trifluoromethylpyrimidinemethanesulphonate

To a suspension of the free base (100 mg) in ethanol was addedmethanesulphonic acid (30 mg) and the resulting clear solution stirredat room temperature for 2 hours. The solution was evaporated to dryness,and the resulting solid triturated with ether, filtered, and dried invacuo, 107 mg, m.pt. 253°-256° C.

8. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-trifluoromethylpyrimidinehydrochloride

To a solution of the free base (150 mg) in methanol was added etherealhydrogen chloride. After stirring, the solvent was evaporated to drynessand the resulting solid triturated with ether, filtered, and dried invacuo, 160 mg, m.pt. 233°-236° C.

EXAMPLE 15 Synthesis of2,4-Diamino-5-(2,3-dicholorophenyl)-6-methylpyrimidine

This compound was made in an analogous manner to the compound of Example6 from 2,3-dichlorophenylaceonitrile, m.pt. 245°-247° C.

EXAMPLE 16 Synthesis of2,4-Diamino-5-(2,3-dichlorophenyl)-6-methoxymethyl pyrimidine

1. Preparation of 2-(2,3-dichlorophenyl)-4-methoxy-3-oxo-butyronitrile

To a stirred refluxing solution of NaOEt (from 1.38 gms Na) in EtOH (25ml) was added a mixture of ethyl methoxyacetate (8.85 gms) and2,3-dichlorophenylacetonitrile (Example 14.3) (9.3 g) dissolved in DME(20 ml) during 5 minutes. After 5 hours a precipitate had appeared(sodium salt of product). The mixture was cooled and filtered, thefiltrate evaporated to dryness in vacuo and the residue partitionedbetween ether and water (the ether phase was discarded). The aqueousresidue was acidified with 2N H₂ SO₄ and extracted with ether (2×). Thecombined Et₂ O extracts were washed with water, dried over MgSO₄,filtered and evaporated in vacuo to give a yellow solid (a). The sodiumsalt (above) was dissolved in water and the solution extracted withether and discarded. The aqueous solution was acidified with 2N H₂ SO₄and extracted with ether. The ether extract was washed with water, driedover MgSO₄, filtered and evaporated in vacuo to give a white solid (b).

The above products (a) and (b) were combined to give a yield of 10.4 gmswhich was used without further purification. Single spot by TLC (19:1CH₂ Cl₂ : MeOH) Rf 0.35.

2. Preparation of 2-(2,3-dichlorophenyl)-3,4-dimethoxybut-2-enonitrile

To a stirred solution of the above nitrile (9.4 gms) in ether was addedin portions diazomethane (0.4-0.45M) in ether. Initially vigorousfrothing occurred and after further addition no immediate reaction wasproduced. The mixture was left stirring at room temperature for 3 hoursand evaporated in vacuo, into AcOH to give the enol ether.

3. Preparation of2,4-Diamino-5-(2,3-dichlorophenyl)-6-methoxymethylpyrimidine

To a solution of NaOEt (from 0.92 gms Na) in EtOH (40 ml) was addedguanidine hydrochloride (3.44 gms). A solution of the enol ether (above)in EtOH (30 ml) was added and the mixture refluxed for ca. 3 hours.After cooling, the solvent was evaporated off in vacuo and the residuetreated with 5N NaOH (ca. 50 ml). The red solid was filtered off,dissolved in AcOH (ca. 20 ml), diluted with water (40 ml), treated withcharcoal, and filtered. The filtrate (yellow solution(was made alkalinewith 2N NaOH, and the white precipitate filtered off, dried andrecrystallised from EtOH, 4.39 gms, mp. 237°-240° C.

EXAMPLE 17

3. Preparation of 2,4-Diamino-5-(1-naphthyl)pyrimidine

To a solution of NaOEt (from 1.45 gms Na) in ethanol (60 ml (at roomtemperature under N₂ was added 1-naphthylacetonitrile (Aldrich, 10.02gms). After stirring for 10 minutes, ethyl formate (8.88 gms) was addedand the mixture stirred at reflux for 5 hours. The mixture was cooled,the solvent evaporated, and the residue triturated with Et₂ O beforefiltering and drying the solid in vacuo (6.86 gms).

The above solid was dissolved in DMF (45 ml), methyliodide (5.4 gms)added, and the reaction vessel sealed before stirring the contents at40° C. for 4 hours. The solvent was then removed in vacuo, and theresidue partitioned between EtOAc and water. The organic phase waswashed with water, dried over MgSO₄, filtered, and the solventevaporated in vacuo to leave the crude product as a viscous reddish oil(5.4 gms).

To a solution of NaOEt (from 1.19 gms of Na) in ethanol (80 ml) wasadded guanidine hydrochloride (4.94 gms). After stirring for a further 5minutes, the above intermediate in ethanol was added and the resultingmixture stirred at reflux for 3.5 hours. After copling, the solvent wasremoved in vacuo and the residue partitioned between CHCl₃ and water.The organic phase was washed with water, dried over MgSO₄, filtered andthe solvent evaporated to leave a pale yellow solid. Chromatography onSiO₂ eluting with CHCl₃ to 4% CHCl₃ :MeOH, followed by recrystallisationfrom ethanol gave the desired product as a white solid. 2.82 gms, mp.171°-3° C.

EXAMPLE 18 Preparation of2,4-Diamino-5-(2,3-dichlorophenyl)-6-fluoromethyl pyrimidine

1. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-(diethoxymethyl)pyrimidine

To a stirred refluxing solution of NaOEt (from 1.38 g sodium) in ethanol(25 ml) was added over 5 minutes a mixture of ethyl diethoxyacetate(13.21 g; 75 mmol) and (Example 14.3) 2,3-dichlorophenylacetonitrile(9.3 g; 50 mmol) in dry dimethoxyethane (20 ml). After 4 hours cooledand evaporated in vacuo. The residue was partitioned between water (100ml) and ether (100 ml), the ether phase discarded and the aqueousresidue acidified with 1N H₂ SO₄. Extraction with CH₂ Cl₂ gave the acylacetonitrile (13.47 g), which was used without further purification.

To a stirred solution of the above acyl acetonitrile in ether (100 ml),cooled on ice was added in portions a solution of diazomethane (ca., 3g) in ether. After 2 hours the solution was evaporated in vacuo to givethe desired enol ether as an oil, which was used without furtherpurification.

To a solution of NaOEt (from 1.4 g sodium) in ethanol (50 ml) was addedguanidine hydrochloride (4.89 g; 50 mmol). A solution of the above enolether in ethanol (20 ml) was added and the mixture refluxed for 4 hourscooled, and concentrated in vacuo to ca. 30 ml and diluted with water togive a dark purple solid which was filtered, dissolved in CH₂ Cl₂,washed with water, dried over MgSO₄ and evaporated in vacuo. The residuewas triturated with ethanol (50 ml) and filtered to give the desiredproduct (8.4 g) which was used without further purification. (mp.214°-217° C.).

2. 2,4-Diamino-5-(2,3-dichlorophenyl)pyrimidine-6-carboxaldehyde

A mixture of the above acetal (7 g) and 0.4M HCl (150 ml) was refluxedwith stirring for 1 hour, cooled on ice and neutralised with 2M NaOH.The mixture was filtered, washed with water and dried in air to give thedesired product (6.2 g), which was used without further purification.

3. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine

To a stirred solution of the above aldehyde (2.8 g; 10 mmol) in amixture of dimethoxyethane (15 ml) and ethanol (15 ml) was added inportions sodium borohydride (110 mg; 3 mmol). After 30 minutes thesolution was treated with water (50 ml) and a few drops of acetic acidadded to destroy excess borohydride. Extracted with dichloromethane(2×50 ml), washed with water and the extract was then dried over MgSO₄.Evaporation of the solvent in vacuo gave a pink solid, which wastriturated with ether, filtered and dried (1.6 g). Recrystallisationfrom methanol (50 ml) gave the desired product as fine colourlesscrystals. 0.65 g, m.p. 173°-6° C.

4. 2,4-Diamino-5-(2,3-dichorophenyl)-6-fluoromethylpyrimidine

To a stirred suspension of2,4-diamino-5-(2,3-dichlorophenyl)-6-hydroxymethylpyrimidine (185 mg; 1mmol) in dry dichloromethane (25 ml), under nitrogen at -70° C., wasadded dropwise diethylaminosulphur trifluoride (263 μl; 2 mmol). Themixture was allowed to warm to 0° C. and kept at this temperature for 4hours. After cooling to -70° C. the mixture was quenched with aqueoussodium bicarbonate, extracted with dichloromethane (2×50 ml), washedwith saturated brine and dried (MgSO₄). Concentration gave a colourlessgum (0.2 g). Chromatography on silica gel, eluting with 0.01:1:19 Et₃N:MeOH:CH₂ Cl₂ gave the desired product which was triturated with CCl₄and dried in vacuo. 111 mg, mp. 224°-6° C.

EXAMPLE 19 2,4-Diamino-5-(2,3-dichlorophenyl)-6-phenoxymethylpyrimidine

To a stirred solution of NaOEt (from 1.38 g sodium), in ethanol (70 ml)at reflux, was added over 10 minutes a mixture of2,3-dichlorophenyl-acetonitrile (9.3 g) and ethyl phenoxyacetate (13.5g) in dry dimethoxyethane (50 ml). After stirring at reflux for 3 hoursthe mixture was cooled, filtered and the solvents evaporated in vacuo.The residue was dissolved in water, washed with ether (discarded),acidified with 2N hydrochloric acid and extracted with dichloromethane.The combined extracts were washed with brine, dried (MgSO₄) andevaporated in vacuo to leave a tan coloured solid (8 g), which was usedwithout further purification.

To a suspension of the crude acyl acetonitrile (8 g) in ether (150 ml)was added in portions an excess of a solution of diazomethane in ether.After stirring for 1 hour at room temperature the solution wasconcentrated in vacuo to give the enol ether, which was used withoutfurther purification. .

To a solution of sodium ethoxide (from 0.63 g sodium) in ethanol (25 ml)at room temperature was added guanidine hydrochloride (2.39 g). After 15minutes a solution of the above enol ether in ethanol (25 ml) was addedand the mixture stirred at reflux for 4 hours. After cooling the solventwas evaporated in vacuo. The residue was suspended in 2N NaOH (75 ml),filtered, washed with water, dried in air and recrystallised fromethanol to give the desired product as a colourless solid. 3.82 g, mp.211°-213° C.

EXAMPLE 202,4-Diamino-5-(2,3-dichlorophenyl)-6-methylthiomethylpyrimidine

To a stirred solution of NaOEt (from 1.38 g sodium), in ethanol (25 ml)at reflux, was added over 5 minutes a mixture of2,3-dichlorophenylacetonitrile (9.3 g) and ethyl methylthioacetate(10.07 g) in dry dimethoxyethane (20 ml). After stirring at reflux for 5hours the mixture was cooled on ice, acidified with acetic acid (5 ml),poured into cold water and extracted with dichloromethane. The combinedextracts were washed with water, dried (MgSO₄) and concentrated to givea yellow oil which was used without further purification.

The crude acyl acetonitrile was heated under N₂ with triethylorthoformate (40 ml) at 140°-150° C. for 4 hours, distilling off lowboiling material. After cooling, the mixture was concentrated in vacuoto leave a dark oil (15.2 g). The oil was dissolved in ethanol (20ml)and added to a mixture of guanidine hydrochloride (4.8 g) and sodiumethoxide (from 1.38 g sodium) in ethanol (50 ml). After stirring atreflux for 4 hours the mixture was cooled and concentrated in. vacuo.The residue was shaken with 5M NaOH to give a dark oil, which wasextracted with dichloromethane, washed with water and dried (MgSO₄).Concentration in vacuo left a dark gum. The desired product crystallisedfrom ethanol (20 ml) as a light tan solid, 0.57 g, mp. 205°-7° C.

EXAMPLE 21A Preparation of 2,4-Diamino-5-(2,3-dichlorophenyl)pyrimidine

a. 2-(2,3-dichlorophenyl)-3-oxo-propionitrile

To a solution of NaOEt (from 3.63 gms Na) in ethanol (500 ml) was added2,3-dichlorophenylacetonitrile (Example 14.3) in ethanol (150 ml). Ethylformate (16.67 gms) was then added and the mixture stirred at 80° C. for45 minutes, before adding a further quantity of ethyl formate (2.78gms). After stirring at 80° C. for a further 1.5 hours, the precipitatewas filtered off and dried in vacuo. The solid was dissolved in water,filtered, acidified with concentrated hydrochloric acid and theprecipitate filtered off and dried in vacuo, 14.35 gms, 45% yield.

b. A solution of the above product, ethylene glycol (9.19 gms) andp-toluene-sulphonic acid (8.9 gms) in toluene (100 ml) was stirred atreflux, with the water being collected in a Dean and Stark trap. Aftercooling, the solution was washed with water, 1N NaOH and water beforedrying over MgSO₄. Evaporation of the solvent left an oil (20.17 gms)which was dissolved in EtOH (70 ml). After standing for 1 hour the creamprecipitate was filtered off and dried in vacuo (10.44 gms).

c. To a solution of NaOMe (5.1 gms) in ethanol (75 ml) was addedguanidine hydrochloride (8.2 gms). After stirring for 30 minutes theNaCl was filtered off, the above acetal added and the mixture stirred atreflux for 1 hour. The solvent was then concentrated and the productfiltered off. Recrystallisation from ethanol gave the product as a whitesolid, 7.67 gms , 70% yield, mp. 212.5°-214° C.

The diamino-pyrimidine (6.12 gms) was dissolved in ethanol (250 ml),concentrated hydrochloric acid (2.07 ml) added, and the suspensionchilled for 2 hours. The precipitate was then filtered off and dried togive the hydrochloride salt, 5.52 gms.

EXAMPLE 21B

a. 2,3-Dichlorophenylacetic acid

Concentrated hydrochloric acid (100 ml) was poured onto crushed ice (150ml), the solution added to 2,3-dichlorophenylacetonitrile (30.6 gms),and the mixture refluxed for 3 hours. After cooling, the mixture wasdiluted with water (500 ml), extracted with EtOAc (600 ml) and theorganic phase washed with brine before drying over MgSO₄. Evaporation ofthe solvent left a white solid, 31.3 gms.

b. Ethyl 2,3-dichlorophenylacetate

To a suspension of the acid in ethanol (200 ml) was added concentratedH₂ SO₄ (1 ml) and the mixture stirred at reflux for 3 hours. Aftercooling, the solvent was evaporated and the residue treated withconcentrated NH₄ OH (3 ml) in water (50 ml). The organic phase wasextracted into CH₂ Cl₂, dried over MgSO₄, and the solvent evaporated toleave a clear liquid, 19.88 gms.

c. Ethyl-2-(2,3-dichlorophenyl)-3-N-morpholino-acrylate

To a mixture of the ester, morpholine (40.7 gms) and ethyl orthoformate(69.24 gms) was added acetic anhydride (0.5 ml) and the resulting paleyellow solution stirred at reflux for 3 hours. After cooling, themixture was concentrated in vacuo. A white precipitate started to form,and this was filtered off before further concentrating the filtrate togive a brownish clear oil. Standing overnight in vacuo gave a yellowsolid, 34.34 gms.

d. 5-(2,3-dichlorophenyl)isocytosine

To the above ester was added guanidine hydrochloride (26.6 gms) slurriedin sodium 2-methoxyethoxide (from 6.6 gms of Na) in 2-methoxyethanol(150 ml), and the mixture stirred at reflux overnight. After cooling,the mixture was concentrated in vacuo, diluted with water (100 ml) andthen washed with Et₂ O (200 ml). The aqueous phase was acidified withAcOH, and the precipitate filtered off and washed with. EtOH and thenEt₂ O before drying in vacuo, 13.48 gms.

e. N¹ -[4-chloro-5-(2,3-dichlorophenyl)-2-pyrimidinyl]-N², N²-dimethylformamidine

To a mixture of the above isocytosine (14.4 gms) in CH₂ Cl₂ (200 ml) wasadded dropwise during 30 minutes fresh Vilsmeier-Haack reagent (from2.75 equivalents of SOCl₂ and 2.58 equivalents of DMF), and the mixturerefluxed for 6 hours. After cooling, 1N NaOH (250 ml) was added slowly.The aqueous phase was washed with CH₂ Cl₂ and the combined organicextracts washed with brine before drying over MgSO₄. Evaporation of thesolvent and chromatography on SiO₂ gel, eluting with EtOAc gave 13.6gms, mp. 113°-115° C.

f. 2-Amino-4-chloro-5-(2,3-dichlorophenyl)pyrimidine

To the formamidine in EtOH (50 ml) was added ethanolic MeNH₂ (8 equiv.)in EtOH (50 ml), and the mixture sealed in a Parr reaction vessel beforestirring at room temperature for 5 hours. The reaction mixture was thenconcentrated in vacuo, the residue mixed with 1N NaOH (75 ml), filtered,washed with water and dried in vacuo, 11.2 gms, mp. 228°-30° C.

g. 2,4-Diamino-5-(2,3-dichlorophenyl)pyrimidine

To 2-amino-4-chloro-5-(2,3-dichlorophenyl)pyrimidine (6.73 gms) wasadded ethanolic ammonia (30 equiv. in 50 ml EtOH) and the mixture sealedin a Parr reaction vessel and heated to 125° C. for 38 hours. Aftercooling, the mixture was concentrated in vacuo and the residue mixedwith 1N NaOH (75 ml), filtered, washed with water and dried in vacuo,6.14 gms, mp. 208°-211° C.

EXAMPLE 22 Synthesis of2,4-Diamino-5-(2-chlorophenyl)-6-methyl-pyrimidine

This compound was prepared according to JACS, (1951), 73, 3763-70, mp.225° C.

EXAMPLE 23 Synthesis of 2,4-Diamino-5-(2-chlorophenyl)pyrimidine

This compound was prepared according to JACS, (1951, 73, 3763-70, mp.125°-8° C.

EXAMPLE 24 Synthesis of 2,4-Diamino-5-(2-chorophenyl)-6-ethylpyrimidine

Prepared as for Example 22, except that ethyl propionate replaced ethylacetate. mp. 197°-8° C.

EXAMPLE 25 Synthesis of2,4-Diamino-5-(2,4-dichlorophenyl)-6-trifluoromethyl pyrimidine

This compound was prepared in a manner analogous to the compound ofExample 14 from 2,4-dichlorophenylacetonitrile (Aldrich): mp.220.5°-221° C.

EXAMPLE 26 Synthesis of6-Benzyloxymethyl-2,4-diamino-5-(2,4-dichlorophenyl)pyrimidine

This compound was prepared in a manner analogous to the compound ofExample 16 from 2,4-dichlorophenylacetonitrile and ethylbenzyloxyacetate, 3.77 gms, mp. 171°-172° C.

EXAMPLE 272-(4-methylpiperazin-1-yl)-4-amino-5-(2,4-dichlorophenyl)pyrimidine

A) A solution of 55.7 g (0.4 equiv) of S-methylisothiourea sulphate in280 ml of water was prepared and gently heated on a steam bath withstirring. Then 40 g (0.4 mol) of N-methyl-piperazine was slowly drippedinto the solution while sweeping the flask out with nitrogen. Theevolved gases were collected in several portions of a solution of 132 gof mercuric chloride in 400 ml of ethanol, which caused evolvedmethylmercaptan to be precipitated as methylmercuric chloride. After theaddition of the N-methylpiperazine was complete, the reaction wascontinued until no more methylmercuric chloride precipitated. Thereaction mixture was then concentrated in vacuo and chilled which causedthe N-methyl-N'-amidinopiperazine sulphate to crystallise; 50.79 g wascollected.

B) A mixture of 76.3 g (0.356 mol) ofα-formyl-2,4-dichlorophenylacetonitrile, 63.7 g of isoamyl alcohol, 0.36g of p-toluenesulphonic acid, 895 ml of toluene, and 10 drops ofconcentrated sulphuric acid were heated under reflux for 20 hours in thepresence of a Dean and Stark trap to remove water formed in thereaction. Then an equal portion of i-amyl alcohol and a few drops ofsulphuric acid were added, and the reaction was heated for another 20hours, until the theoretical amount of water had been collected. Thesolution was cooled.

C) An 8.2 g portion of sodium was dissolved in 500 ml of absoluteethanol, and 50 g of N-methyl-N'-amidinopiperazine sulphate was added.The mixture was allowed to stir for 10 minutes. This was then added tosolution B. The mixture was refluxed with stirring for 6 hours, allowedto stand overnight and the solvent removed in vacuo. The residue wasthen extracted with dilute hydrochloric acid, which dissolved most ofit. The solution was extracted three times with ether, followed byneutralization of the aqueous fraction, which precipitated a gum whichsolidified upon standing overnight; weight 30 g. This was crystallisedrepeatedly from 50% ethanol with the aid of decolourising charcoal. Veryslow cooling was required in order for crystals to be formed; mp. 137°C.

Anal. Calcd for Cl₁₅ H₁₇ Cl₂ N₅ ; C, 53.27; H, 5.07; N, 20.71; Found: C,53.58; H, 5.14; N, 20.40.

EXAMPLE 28 Synthesis of2,4-Diamino-5-(2,5-dichlorophenyl)-6-trifluoromethyl pyrimidine

This compound was prepared in a manner analogous to the compound inExample 14 from 2,5-dichlorobenzyl alcohol (Lancaster Synthesis, 48.26g) to give the title compound in a yield of 3.85 gms, mp. 215°-217° C.

EXAMPLE 29 Preparation of2,4-Diamino-5-(2,3,5-trichlorophenyl)pyrimidine

Guanidine hydrochloride (3.20 g) was added to a solution of sodiumethoxide (from 848 mg sodium) in ethanol (52 ml). The resulting whitesuspension was stirred at room temperature for 10 minutes. The enolether from Example 3.2 (4.40 g) was added and the resulting mixturestirred at reflux for 3.5 hours. After cooling, the suspension wasfiltered, and the filtrate evaporated to dryness in vacuo.Chromatography on silica gel eluting with CHCl₃ to 3% MeOH--CHCl₃ gavethe desired product which was triturated with ether and. dried in vacuo.Yield=2.01 g, mp. 246°-249° C.

EXAMPLE 30 Synthesis of4-Amino-5-(3-bromophenyl)-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidine

To a solution of NaOEt (from 0.92 g of sodium) in ethanol (75 ml) wasadded 3-bromophenylacetonitrile (Aldrich, 7.85 g) and ethyl acetate(3.52 g). The mixture was heated under reflux for 6 hours. Aftercooling, the mixture was concentrated and the residue was dissolved inwater. The aqueous phase was washed with ether, acidified with 2N HCland extracted with ether. The extracts were bulked, dried (MgSO₄) andevaporated, 3.8 g, mp. 97°-103° C.

The resulting ketone (3.7 g), ethylene glycol (5 ml) andp-toluenesulphonic acid (100 mg) were heated under reflux in toluene(100 ml) in a Dean & Stark apparatus for 3.5 hours. The mixture wascooled, concentrated and water was added to the residue. The product wasextracted with ether and the extracts were bulked, dried (MgSO₄) andevaporated, 4.03 g, mp. 68°-71° C.

To a solution of NaOEt (from 0.28 g of sodium) in ethanol (30 ml) wasadded N-methylpiperazinoformamidine hydriodide (2.7 g). After stirringfor 10 minutes, the ketal (1.41 g) was added and the mixture was stirredat reflux for 4 hours. After cooling the suspension was filtered, andthe filtrate was concentrated. The residue was purified bychromatography on SiO₂ gel, eluting with 10% MeOH/CHCl₃ to give thedesired product, 0.48 g, mp. 120°-122° C.

EXAMPLE 31 synthesis of2,4-Diamino-5-(1-naphthyl)-6-trifluoromethylpyrimidine

This compound was prepared in a manner analogous to the compound inExample 14 from 1-naphthylacetonitrile (Aldrich, 10 gms), to give thetitle compound in a yield of 0.6 g gms, mp. 224°-226° C.

EXAMPLE 32 Preparation of2-Amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine

1. Ethyl 2,4-dichlorophenylacetate

2,4-Dichlorophenylacetonitrile (27.9 g, 150 m.mol) was suspended in 2NNaOH (400 ml) and the mixture refluxed for 4 hours. The cooled reactionmixture was extracted with ether (2×200 ml) acidified to pH3 and thesolid filtered and dried (22 g, 70%).

The product (20 g) was dissolved in EtOH (300 ml) and concentrated H₂SO₄ (5 ml) added carefully. The mixture was refluxed for 7 hours. Thecooled reaction mixture was evaporated under reduced pressure and theresidue partitioned between CH₂ Cl₂ and water (30 ml each). The organiclayer was extracted with saturated NaHCO₃ solution (200 ml), washed withwater (100 ml), dried and evaporated in vacuo to give ethyl2,4-dichlorophenylacetate as an oil (22.29 g, 89.5%).

2. Diethyl 2,4-Dichlorophenyl malonate

Sodium(1.86 g, 0.081M) was added in portions to absolute ethanol (150ml) with stirring. After all the sodium had dissolved a solution ofethyl 2,4-dichlorophenylacetate (20 g) in diethyl carbonate (50 ml) wasadded dropwise. The reaction mixture was heated until EtOH distilledover. The rate of addition was controlled such that it equalled the rateof distillation. After the completion of addition the reaction mixturewas heated and distilled for further 4 hours. The cooled reactionmixture was partitioned between water (300 ml) and EtOAc (300 ml) andthe organic layer dried and evaporated in vacuo to give a yellow oil (21g, 85%).

3. 2-Amino-5-(2,4-dichlorophenyl)-4,6-dihydroxypyrimidine

Sodium (4.529, 0.196M) was added in portions to ethanol (150 ml). Afterall the sodium had dissolved guanidine hydrochloride (12.44 g, 0.13M)was added followed by diethyl 2,4-dichlorophenyl malonate(20 g,0.0655M). The mixture was refluxed for 6 hours, EtOH was removed underreduced pressure and the residue partitioned between 2N NaOH (400 ml)and EtOAc (400 ml). The aqueous layer was acidified with concentratedhydrochloric acid with cooling and the precipitated solid was filteredand dried (11 g, 62%).

4. 2-Amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine

A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dihydroxypyrimidine (10g), phosphoryl chloride (100 ml) and dimethylaniline (1.5 ml) wasrefluxed for 6 hours. The cooled reaction mixture was carefully added tocrushed ice and the insoluble solid was filtered and washed with 2N HCl,followed by water. The solid was resuspended in water, neutralised (0.88NH₄ OH) with cooling, and the mixture stood overnight at roomtemperature. The insoluble solid was filtered, dried and purified byflash column chromatography to give the title compound (2.5 g, 22%), mp.211°-213° C. Microanalysis:

Calcd: C, 38.83; H, 1.6; N, 13.59; Found: C, 38.59; H, 1.53; N, 13.40.

EXAMPLE 33 Synthesis of2,4-Diamino-6-chloro-5-(2,4-dichlorophenyl)-pyrimidine

A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichloropyrimidine (0.5g) (Example 32) EtOH saturated with ammonia (20 ml) and copper powder(0.05 g) was heated in an autoclave at 180° C. for 18 hours. The cooledreaction mixture was filtered, evaporated and the residue purified byflash column chromatography to give the title compound (0.12, 25%), mp.219° C. Microanalysis:

Calcd: C, 40.82; H, 2.55; N, 19.05; Found: C, 41.27; H, 2.46; N, 18.74.

EXAMPLE 34 Synthesis of2-Amino-4-chloro-5-(2,4-dichlorophenyl)-6-methylthio pyrimidine

A mixture of 2-amino-5-(2,4-dichlorophenyl)-4,6-dichlorohyrimidine (0.5g) (Example 32) THF (15 ml), methanethiol sodium salt (0.113 g), copperpowder (0.05 g) and tris[2-(2-methoxyethoxy)ethyl]amine (0.1 g) washeated in an autoclave at 180° C. for 18 hours. The cooled reactionmixture was filtered, evaporated and the residue purified by flashcolumn chromatography to give the title compound (0.262 g, 52%), mp.201°-202° C. (softens at 196° C.). Microanalysis:

Calcd: C, 41.19; H, 2.50; N, 13.10; Found: C, 41.10; H, 2.52; N, 12.77.

EXAMPLE 35 Synthesis of2,4-Diamino-5-(2,4-dichlorophenyl)-6-methylthiopyrimidine

A mixture of 2-amino-4-chloro-5-(2,4-dichlorophenyl)-6-methylthiopyrimidine (0.5 g) (Example 32) EtOH saturated with ammonia (20 ml),copper powder (0.05 g) and tris[2-(2-methoxyethoxy)ethyl]amine (0.01 g)was heated in an autoclave at 180° C. for 18 hours. The cooled reactionmixture was filtered, evaporated and the residue purified by flashcolumn chromatography to give the title compound (0.11 g, 23.5%), mp.191°-192° C. Microanalysis:

Calcd: for 0.2 hydrate: C, 43.33; H, 3.41; N, 18.38; Found: C, 43.37; H,3.23; N, 18.33.

EXAMPLE 364-Amino-5-(3,5-dichlorophenyl)-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidin

a. 3,5-Dichlorophenylacetonitrile

A mixture of 3,5-dichlorobenzyl alcohol (Aldrich, 25 g) , thionylchloride (100 ml) and DMF (0.5 ml) was stirred and refluxed for 4 hours.After cooling the mixture was concentrated in vacuo, the residue wastaken up in ether, washed with saturated aqueous NaHCO₃ and brine, dried(MgSO₄) and concentrated in vacuo to give 3,5-dichlorobenzyl chloride asa light yellow solid, which was used without further purification, 28 g,mp. 32°-36° C.

To a vigorously stirred solution of 3,5-dichlorobenzylchloride (28 g) indichloromethane (150 ml) was added a mixture of KCN (27.5 g) andtetrabutylammonium hydrogen sulphate (2.38 g) in water (110 ml). Afterstirring at room temperature for 22 hours, the mixture was diluted withdichloromethane, the organic phase washed with water and concentrated invacuo to leave an oil. Filtration through silica with toluene followedby concentration then trituration with hexane gave the desired productas a colourless solid. 15.8 g, mp. 31°-32° C.

b.4-Amino-5-(3,5-dichlorophenyl)-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidine

To a stirred solution of NaOEt (from 0.69 g sodium), in ethanol (25 ml)at reflux, was added over 5 minutes a mixture of3,5-dichlorophenylacetonitrile (9.3 g) and ethyl acetate (3.3 g) in drydimethoxyethane (10 ml). After stirring at reflux for 4 hours, themixture was cooled on ice, acidified with acetic acid, poured into coldwater and extracted with dichloromethane. The combined extracts werewashed with water and concentrated to give an oil. Trituration withhexane gave 2-(3,5-dichlorophenyl)-3-oxobutyronitrile as a colourlesssolid (4.15 g).

To a solution of the acyl acetonitrile (4.1 g) in ether (100 ml) wasadded in portions an excess of a solution of diazomethane in ether.After stirring for 2 hours at room temperature the solution wasconcentrated in vacuo to give the enol ether.

To a stirred solution of NaOEt (from 0.72 g sodium) in ethanol (25 ml)was added N-methylpiperazinoformamidine hydriodide (7.29 g). After 10minutes a solution of the above enol ether in ethanol (25 ml) was addedand then stirred and refluxed for 4.5 hours. After cooling the solventwas evaporated in vacuo and the residue shaken with 2N NaOH (50 ml). Thesolid was filtered off, washed with water, dried in air andchromatographed (silica; 1:9 MeOH:CHCl₃) to give the desired product asa colourless solid, 1.6 g, mp. 164°-166° C.

EXAMPLE 37 Preparation of2,4-Diamino-5-(2,5-dichlorophenyl)-6-methylpyrimidine

This compound was made in an analogous manner to the compound of Example6 from 2,5-dichlorobenzylalcohol (Lancaster Synthesis). Mp. 226°-228°C.: TLC (SiO₂ :CHCl₃ /MeOH, 9:1) Rf=0.24.

EXAMPLE 38 Preparation of2,4-Diamino-5-(3,4-dichlorophenyl)-6-trifluoromethylpyrimidine

This compound was made in an analogous manner to the compound of Example4, from 3,4-dichlorophenylacetonitrile (Aldrich) mp. 252°-254.5° C.: TLC(SiO₂ ; methanol/chloroform, 1:9) Rf=0.38.

EXAMPLE 39 Preparation of2,4-Diamino-5-(2,3-dichlorophenyl-4-nitrophenyl)pyrimidine

This compound was made in an analogous manner to the compound of Example5 from 2,4-diamino-5-(2,3-dichlorophenyl)pyrimidine (Example 21). Thereaction gave a mixture of the 4-nitro and 5-nitro derivatives fromwhich the title compound was separated by column chromatography (SiO₂,EtOAc), mp. 237°-9° C. Also separated in this manner was2,4-diamino-5-(2,3-dichloro-5-nitrophenyl)pyrimidine, mp. 264°-6° C.

EXAMPLE 40 Preparation of2,4-Diamino-5-(2,4-dichlorophenyl)-6-(diethoxymethyl)pyrimidine

This compound was prepared in a manner analogous to2,4-diamino-5-(2,3-dichlorophenyl)-6-(diethoxymethyl)pyrimidine (Example18.1) from 2,4-dichlorophenylacetonitrile, mp. 225° C.

EXAMPLE 41 Preparation of2,4-Diamino-5-(3,5-dichlorophenyl)-6-methylpyrimidine

This compound was prepared in a manner analogous to the compound ofExample 6 from 3,5-dichlorophenylacetonitrile (Aldrich). mp. 242°-244°C.

EXAMPLE 42 Preparation of2,4-Diamino-5-(2,3-dichlorophenyl)-6-trifluoromethyl pyrimidine N-oxide

This compound was made from the compound of Example 14 by reaction withMCPBA in CHCl₃ at room temperature. Mp. 275°-278° C.

EXAMPLE 43 Preparation of2,4-Diamino-5-(2,3-dichlorophenyl)-6-tribromomethyl pyrimidine

This compound was prepared from the compound of Example 15 by reactionwith excess bromine and sodium acetate in acetic acid at reflux. Thetitle compound was separated from a mixture with the compound of Example75 by coloumn chromatography, mp. 210° C. (dec).

EXAMPLE 44 Preparation of2,4-Diamino-5-(2,4-dichlorophenyl)-6-methoxymethyl pyrimidine

This compound was prepared in a manner analogous to Example 2, from2,4-dichlorophenylacetonitrile, mp. 183°-185° C. Single spot on TLC.

EXAMPLE 45 Preparation of2,4-Diamino-5-(2,6-dichlorophenl)-6-methylpyrimidine

This compound was prepared in a manner analogous to Example 6 from2,6-dichlorophenylacetonitrile (Aldrich), mp. 250° C.

EXAMPLE 46 Preparation of2,4-Diamino-5-(2,4-dichlorophenyl)pyrimidine-6-carboxaldehyde

This compound was made from the compound of Example 40 in an analogousmanner to the compound of Example 18.2, mp. >350° C.

EXAMPLE 47 Preparation of2,4-Diamino-5-(2,3-dichloro-4-nitrophenyl)-6-methyl pyrimidine

This compound was made from the compound of Example 15 in an analogousmanner to the compound of Example 39, mp. 265° C. Also obtained fromthis reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methylpyrimidine.

EXAMPLE 48 Preparation of2,4-Diamino-5-(2,4-dichlorophenyl)-6-hydroxyimino methylpyrimidine

This compound was made from the compound of Example 46 by reaction withhydroxylamine hydrochloride in ethanol, mp. 260°-5° C.

EXAMPLE 49 Preparation of2,4-Diamino-5-(2,4-dichlorophenyl)-6-hydroxymethyl pyrimidine

This compound was made from the compound of Example 46 in an analogousmanner to the compound in Example 18.3, mp. 169°-171° C.

EXAMPLE 50 Preparation of 2,4-Diamino-5-(2,3,4-trichlorophenyl)-6-methylpyrimidine

This compound was made from the compound of Example 47 by reduction tothe amine (PtO₂, H₂, AcOH), formation of the diazonium salt (NaNO₂, H₂SO₄), and reaction of this with CuCl (as for Example 57). Sublimes at275° C. Homogenous on TLC (methanol/chloroform, 1:9) Rf=0.36.

EXAMPLE 51 2,4-Diamino-5-(2,6-dichlorophenyl)-6-methoxymethyl-pyrimidine

This compound was prepared in an analogous manner to the compound ofExample 2 from 2,6-dichlorophenylacetonitrile (Aldrich), mp. 204°-207°C.

EXAMPLE 52 Preparation of2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-trichloromethyl pyrimidine

This compound was made from the compound of Example 6 by reacting withNCS in AcOH at 100° C. (AIBN as catalyst), mp. 226°-227° C.

EXAMPLE 53 2,4-Diamino-5-(2,4-dichlorophenl)-6-fluoromethylpyrimidine

1. 2,4-Diamino-6-bromomethyl-5-(2,4-dichlorophenyl)pyrimidine

2,4-Diamino-6-benzyloxymethyl-5-(2,4-dichlorophenyl)pyrimidine (Example26) (6.5 g) was dissolved in a 47% solution of hydrobromic acid inacetic acid (75 ml) and the mixture stirred and heated at 100° C. for 6hours. After standing at room temperature overnight the dihydrobromidesalt was filtered off, washed with ether and dried in vacuo, 6 g.

To a stirred solution of the dihydrobromide salt (0.43 g) indimethylsulphoxide (4 ml) was added dropwise a solution of sodiumbicarbonate (0.84 g) in water (10 ml). After 30 minutes the precipitatewas filtered off, washed with water then ether and dried in vacuo, 0.26g, mp.>270° C. (decomposes).

2. 2,4-Diamino-5-(2,4-dichlorophenyl)-6-fluoromethylpyrimidine

To a solution of2,4-diamino-6-bromomethyl-5-(2,4-dichlorophenyl)pyrimidine (1.04 g) intetramethylene sulphone (4.5 ml) was added cesium fluoride (1 g). Themixture was stirred and heated at 100° C. for 4 hours, cooled, dilutedwith water and extracted with chloroform. The combined extracts werewashed with water, dried (MgSO₄) and concentrated in vacuo. The residuewas chromatographed (silica; 19:1:0.1dichloromethane/methanol/triethylamine) to give the title compound,which was recrystallised from ethanol. 0.19 g, mp. 210°-211° C.

EXAMPLE 54 Preparation of2,4-Diamino-5-[2-chloro-5-(N,N,dimethylsulphamoyl)phenyl]-6-methylpyrimidine

1. 2,4-Diamino-5-(2-chloro-5-nitrophenyl)-6-methylpyrimidine

To a solution of 2,4-diamino-5-(2-chlorophenyl)-6-methyl pyrimidine(11.84 g) (Example 22) in concentrated H₂ SO₄ (100 ml), was addedpotassium nitrate (5.1 g). After stirring at room temperature for 90minutes, the solution was poured onto ice and basified with 10N NaOH.The product was extracted with ethyl acetate, bulked, dried (MgSO₄) andevaporated, 13.9 g, 236°-240° C.

2,4Diamino-5-(5-amino-2-chlorophenyl)-6-methylpyrimidine

A solution of 2,4-diamino-5-(2-chloro-5-nitrophenyl)-6-methyl pyrimidine(13.9 g) in acetic acid (500 ml) was reduced under an atmosphere ofhydrogen in the presence of PtO₂ (0.28 g). The mixture was filteredthrough hyflo and the filtrate was concentrated. The residue wasneutralised with saturated NaHCO₃ solution and the product was extractedwith ethyl acetate, bulked, dried (MgSO₄) and evaporated. Chromatographyon SiO₂ gel, eluting with CHCl₃ 40% MeOH/CHCl₃, gave the desiredproduct, 6 g, mp. 117°-121° C.

3. 2,4-Diamino-5-(2-chloro-5-N,N-dimnthylsulphamoylphenyl)-6-methylpyrimidine

2,4-Diamino-5-(5-amino-2-chlorophenyl)-6-methylpyrimidine (0.25 g) wasdissolved in water (0.8 ml) and concentrated HCl (0.5 ml). To the cooledsolution (below 10° C.) was added a solution of sodium nitrite (0.07 g)in water (0.5 ml). After stirring at room temperature for 2 hours, thesolution was cooled to 5° C. Cupric chloride (0.05 g) and 5.14M SO₂ inacetic acid (0.97 ml) were added and the reaction was stirred at 5° C.overnight. The mixture was filtered and washed with water to give thesulphonyl chloride, 0.23 g.

The sulphonyl chloride (0.16 g) was dissolved in THF (2 ml) aqueousdimethylamine (2 ml) was added. After stirring overnight, the solutionwas diluted with water, extracted with ethyl acetate, bulked, dried(MgSO₄) and evaporated. Chromatography on SiO₂ gel, eluting with 2%MeOH/CHCl₃, gave the desired product, 0.047 g, mp. 283°-285° C.

EXAMPLE 55 Preparation of2,4-Diamino-(3,5-dichlorophenyl)-6-methoxymethyl pyrimidine

This compound was prepared in an analogous manner to the compound inExample 2 from 3,5-dichlorophenylacetonitrile, mp. 228°-230° C.

EXAMPLE 56 Preparation of2,4-Diamino-5-(2,3-dichlorophenyl)-6-hydroxypyrimidine

1. Ethyl-2-cyano-2-(2,3-dichlorophenyl)acetate

Sodium (1.2 g) was added portionwise to ethanol (50 ml) with stirring.After the sodium had dissolved a solution of2,4-dichlorophenylacetonitrile (9.4 g) in diethylcarbonate (25 ml) wasadded dropwise. The reaction mixture was heated until EtOH distilledover. The rate of addition was controlled such that it equalled the rateof distillation. After the completion of the addition, the reactionmixture was heated and distilled for a further 4 hours. The cooledreaction mixture was partitioned between water and EtOAc (300 ml each).The organic layer was dried and evaporated in vacuo and the residue waspurified by flash column chromatography to give the title product. (5 g,39%).

2. 2,4-Diamino-5-(2,3-dichlorophenyl)-6-hydroxypyrimidine

Sodium (1.2 g, 0.052 mol) was added in portions to absolute ethanol (50ml) with stirring. After the sodium had dissolved guanidinehydrochloride (3.69 g, 0.039 mol) was added followed byethyl-2-cyano-2-(2,3-dichlorophenyl)acetate (5 g, 0.0195 mol). Themixture was refluxed for 8 hours, EtOH was removed under reducedpressure and the residue was partitioned between EtOAc and water. TheEtOAc layer was extracted with 2N NaOH and the extract was neutralisedwith 2N HCl with cooling. The precipitated solid was filtered and driedto give the title compound. (0.22 g), mp. 275° C. (decomp).Microanalysis:

Calcd: for 0.25 hydrate: C, 43.56; H, 3.09; N, 20.33; C, 43.76; H, 3.09;N, 20.03.

EXAMPLE 57 Synthesis of2,4-Diamino-5-(2,4,5-trichlorophenyl)-6-methylpyrimidine

a. Preparation of 2-(2,4-dichlorophenyl)-3-oxo-butyronitrile

A solution of 2,4-dichlorophenylacetonitrile (30.00 gms , 161 mmol)(Aldrich) in dry ethyl acetate (36 ml) was added dropwise to anethanolic solution of sodium ethoxide, prepared in situ from sodiummetal (4.90 g , 213 mmol) and dry ethanol (60 ml). This reaction mixturewas refluxed for two hours, allowed to stand overnight at roomtemperature and the ethanol was evaporated. The yellow solid obtainedwas dissolved in water and the resulting solution was extracted twicewith ether. The aqueous layer was chilled and acidified withhydrochloric acid. The crude product was extracted with ether to give23.31 g of white solid.

b. be Preparation of 2,4-diamino-5-(2,4-dichlorophenyl)-6-methylpyrimidine

A solution of crude 2-(2,4-dichlorophenyl)-3-oxo-butyronitrile (23.24gs) in dry toluene (400 ml) was refluxed with ethylene glycol (280 ml)and p-toluenesulphonic acid (8.00 g, 42 mmol) for four hours using aDean and Stark trap. After cooling, the organic phase was washed withsaturated NaHCO₃, dried over MgSO₄, and the solvent evaporated to leavea solid (24.0 gm).

Finely ground guanidine hydrochloride (19.1 g, 200 mmol) was added to anethanolic solution of sodium ethoxide, prepared in situ from sodiummetal (5.0 g, 218 mmol) in dry ethanol (500 ml). A solution of the ketal(25.0 g, 92 mmol) in dry ethanol (10 ml) was added to the guanidinesolution. This mixture was refluxed for two hours and allowed to standovernight at room temperature. The ethanol was evaporated and the crudeproduct recrystallised from hot acetone to give 17.23 g of product, mp.222°-222.5° C.

c. Preparation of2,4-Diamino-5-(2,4-dichloro-5-nitpophenyl)-6-methylpyrimidine

Finely ground potassium nitrate (6.5 g 64 mmol) was added to a solutionof 2,4-diamino-5-(2,4-dichlorophenyl)-6-methylpyrimidine (17.23 g, 64mmol) in concentrated sulphuric acid (150 ml). This mixture was stirredat room temperature for 90 minutes. The reaction mixture was then addedto sodium bicarbonate and ice. The product was extracted with ethylacetate. After the ethyl acetate was removed, a yellow solid wasobtained (30.86 g). A portion of this crude product (7.0 g) was passedthrough a silica flash chromatography column and eluted with ethylacetate to give the pure product (4.81 g).

d. Preparation of2,4-Diamino-5-(5-amino-2,4-dichlorophenyl)-6-methylpyrimidine

2,4-diamino-5-(2,4-dichloro-5-nitrophenyl)-6-methylpyrimidine (4.80 g,15 mmol) was dissolved in glacial acetic acid (18 ml). This solution and10 mg of Adam's catalyst was stirred under an atmosphere of hydrogen atroom temperature for 4 hours. The catalyst was filtered off and theacetic acid was evaporated. The colourless liquid obtained was dissolvedin ethyl acetate and washed 3 times with water. After evaporating theethyl acetate, a white solid was obtained (2.64 g, 9 mmol).

e. Preparation of 2,4-Diamino-5-(2,4,5-trichlorophenyl)-6-methylpyrimide

2,4-diamino-5-(5-amino-2,4-dichlorophenyl)-6-methylpyrimidine (1.95 g, 7mmol) was dissolved in a mixture of concentrated hydrochloric acid (3.6ml) and water (6 ml). The temperature was lowered to 10° C. A chilledaqueous solution (3.6 ml) of sodium nitrite (0.50 g, 7 mmol) was addeddropwise, keeping the temperature at 10° C. This mixture was stirred atroom temperature for 2 hours, then chilled before adding it dropwise toa cold solution of cuprous chloride (1.7 g, 17 mmol) in concentratedhydrochloric acid (50 ml). A grey solid precipitated which was filteredoff and dried. This crude product (2.30 g) was dissolved in ethylacetate and washed twice with ammonium hydroxide solution and once withbrine. After evaporating the ethyl acetate an off-white solid wasobtained (2.04 g). After recrystallisation from 10% methanol inchloroform the pure product was obtained (0.55 g, 2 mmol), mp. 262° C.(dec).

EXAMPLE 58 Synthesis of4-amino-2-(ethylamino)-5-(2,3,5-trichlorophenl)pyrimidine

To a solution of NaOEt (from 0.1 g of sodium) in ethanol (10 ml) wasadded ethylguanidine sulphate (1 g) (Aldrich). After stirring for 10minutes, the enol ether (Example 3.2) (0.486 g) was added and themixture was stirred at reflux for 4 hours. The reaction was leftstanding at room temperature overnight and then filtered. The filtratewas concentrated and the residue was purified by chromatography on SiO₂gel, eluting with CHCl₃ to give the desired product, 0.11 g, mp.149°-152° C.

EXAMPLE 59 2,4-Diamino-5-(2,4-dichlorophenyl)-6-cyanomethyl-pyrimidine

This compound was prepared from2,4-diamino-5-(2,4-dichlorophenyl)-6-bromomethyl-pyrimidine (Example 53)by reaction with sodium cyanide in DMF at room temperature, mp.249°-251° C.

EXAMPLE 602,4-Diamino-5-(2,4-dichlorophenyl)-6-dimethylaminomethylpyrimidine

This compound was prepared from2,4-diamino-5-(2,4-dichlorophenyl)-6-bromomethyl-pyrimidine (Example 53)by reaction with dimethylamine in ethanol at room temperature, mp.170°-172° C.

EXAMPLE 61 2,4-Diamino-5-(2,4-dichorophenyl)-6-cyanopyrimidine

This compound was prepared from the compound of Example 48 by reactionwith trifluoroacetic anhydride in pyridine, mp. 249° C.

EXAMPLE 62 2,4-Diamino-5-(2-chloro-4-fluorophenyl)-6-methylpyrimidine

This compound was prepared in an analogous manner to the compound ofExample 15 from 2-chloro-4-fluorophenylacetonitrile, which was itselfprepared from 2-chloro-4-fluorotoluene (Aldrich, mp. 238° C.

EXAMPLE 63 2,4-Diamino-5-(3,4-dichlorophenyl)-6-methoxymethyl pyrimidine

This compound was prepared in an analogous manner to the compound ofExample 2 from 3,4-dichlorophenylacetonitrile (Aldrich), mp. 204°-206°C.

EXAMPLE 64 2,4-Diamino-5-(2,3-dicholorophenyl)-6-ethylpyrimidine

This compound was prepared in an analogous manner to the compound ofExample 15 from ethyl propionate, mp. 228°-230° C.

EXAMPLE 65 2,4-Diamino-5-(2,4-difluorophenyl)-6-methylpyrimidine

This compound was prepared in an analogous manner to the compound ofExample 6 from 2,4-difluorophenylacetonitrile (Aldrich), mp. 291°-296°C.

EXAMPLE 66 2,4-Diamino-5-(2-naphthyl)-6-methylpyrimidine

This compound was prepared in an analogous manner to the compound ofExample 6 from 2-naphthylacetonitrile (Aldrich), mp. 221°-222° C.

EXAMPLE 67 2,4-Diamino-5-(1-naphthyl)-6-methylpyrimidine

This compound was prepared in an analogous manner to the compound ofExample 6 from 1-naphthylacetonitrile (Aldrich), mp. 224°-225° C.

EXAMPLE 68 2-Hydroxy-4-amino-5-(2,3-dichlorophenyl)pyrimidine

This compound was prepared from the compound of Example 21 by reactionwith sodium nitrite in 1N H₂ SO₄ at reflux to give a mixture of thetitle compound and the compound of Example 21B.d. The title compound wasseparated by column chromatography, mp. 330°-334° C.

EXAMPLE 692-Amino-4-ethoxy-5-(2,4-dichlorophenyl)-6-methylthiopyrimidine

This compound was made from the compound of Example 32.4 by reactionwith methanethiol sodium salt in ethanol, mp. 123°-124° C.

EXAMPLE 702,4-Diamino-5-(2,3,5-trichlorophenyl)-6-hydroxymethylpyrimidine

This compound was made from the compound of Example 2 by reaction withtrimethylsilyl iodide in sulpholane at 80° C., mp. 101°-105° C.

EXAMPLE 71 2,4-Diamino-5-(2,3,5-trichlorophenyl)-6-fluoromethylpyrimide

This compound was prepared in an analogous manner to the compound ofExample 18 from2,4-diamino-5-(2,3,5-trichlorophenyl)-6-hydroxymethylpyrimidine, mp.215°-217° C.

EXAMPLE 72 2,4-Diamino-5-(2,4-dichlorophenyl)-6-carbamoylpyrimidine

This compound was prepared from the compound of Example 61 by reactionwith concentrated sulphuric acid at room temperature, mp. 298°-299° C.

EXAMPLE 73 2,4-Diamino-5-(2,4-dichlorophenyl)pyrimidine-6-carboxylicacid

This compound was prepared from the compound of Example 46 reaction withpotassium permanganate, mp. 227° C.

EXAMPLE 74Ethyl-2,4-diamino-5-(2,4-dichlorophenyl)pyrimidine-6-carboxylate

This compound was prepared from the compound of Example 73 by refluxingin ethanol in the presence of concentrated sulphuric acid, mp. 177.5° C.

EXAMPLE 75 2,4-Diamino-5-(2,3-dichlorophenyl)-6-dibromomethylpyrimidine

This compound was prepared from the compound of Example 15 by reactionwith 2 eq NBS in CCl₄ and AIBN as initiator. The title compound wasseparated from a mixture with the compound of Example 43 by columnchromatography, mp. 270° C. (dec).

EXAMPLE 76 2-Dimethylamino-4-amino-5-(2,4-dichlorophenyl)pyrimidine

This compound was prepared in an analogous manner to the compound ofExample 10 from 2,4-dichlorophenylacetonitrile (Aldrich), mp. 151° C.

EXAMPLE 772-Dimethylamino-4-amino-5-(3,4-dichlorophenyl)-6-methylpyrimidine

This compound was made in an analogous manner to the compound of Example13 from 3,4-dichlorophenylacetonitrile.

EXAMPLE 78 2-Piperidyl-4-amino-5(2,4-dichlorophenyl)pyrimidine

This compound was prepared in an analogous manner to the compound ofExample 76 from 1-piperidinecarboxamidine sulphate (Bader), mp. 169° C.

EXAMPLE 79 2-Methylamino-4-amino-5-(2,3,5-trichlorophenyl)pyrimidine

This compound was prepared in an analogous manner to the compound ofExample 58 from 1-methyl-guanidine hydrochloride (Aldrich), mp.155°-157° C.

EXAMPLE 80 2,4-Diamino-5-(2-chloro-5-bromophenyl)-6-methylpyrimidine

This compound was prepared in a similar manner to the compound ofExample 54 by reaction of the diazonium salt with cuprous bromide, mp.212°-216° C.

EXAMPLE 81 2,4-Diamino-5-(2-chloro-5-iodophenyl)-6-methylpyrimidine

This compound was prepared in a similar manner to the compound ofExample 54 by reaction of the diazonium salt with potassium iodide, mp.232°-234° C.

EXAMPLE 82 2,4-Diamino-5-(2-chloro-5-cyanophenyl)-6-methylpyrimidine

This compound was prepared in a similar manner to the compound ofExample 54 by reaction of the diazonium salt with cuprous cyanide, mp.239°-241° C.

EXAMPLE 83 2,4-Diamino-5-(2-chloro-5-fluorophenyl)-6-methylpyrimidine

This compound was prepared in a similar manner to the compound ofExample 54 by way of the diazonium tetrafluoroborate salt, mp. 195°-197°C.

EXAMPLE 842,4-Diamino-5-(2-chloro-5-methylthiophenyl)-6-methylpyrimidine

This compound was prepared in a similar manner to the compound ofExample 54 by reaction of the diazonium salt with methanethiol in thepresence of copper powder, mp. 194°-198° C.

EXAMPLE 85 2-Amino-4,6-di(methylthio)-5-(2,4-dichlorophenyl)pyrimidine

This compound was prepared from the compound of Example 32.4 by reactionwith methanethiol sodium salt in methanol in the presence oftris[2-(2-methoxyethoxy)ethyl]amine and copper powder, mp. 164°-165° C.

EXAMPLE 862,4-Diamino-5-(2-chloro-5-methanesulphonylaminophenyl)-6-methylpyrimidine

This compound was prepared from2,4-diamino-5-(2-chloro-5-aminophenyl)-6-methylpyrimidine from Example54 by reaction with methanesulphonylchloride in pyridine, mp. 234°-240°C.

EXAMPLE 87 2,4-Diamino-5-(2,3-dichlorophenyl)-1-methylpyrimidiniumiodide

This compound was prepared from the compound of Example 21 and methyliodide, mp. 280°-284° C.

EXAMPLE 88 2-Amino-4-methylamino-5-(2,3-dichlorophenyl)pyrimidine

This compound was prepared in an analogous manner to the compound ofExample 21B.g by reaction with methylamine in ethanol, mp. 233°-237° C.

EXAMPLE 89 2-Amino-4-dimethylamino-5-(2,3-dichlorophenyl)pyrimidinehydrochloride

This compound was prepared in an analogous manner to the compound ofExample 21B.g by reaction with dimethylamine in ethanol and subsequentconversion to the hydrochloride salt, mp. 295°-300° C.

EXAMPLE 90 2-Amino-4-chloro-5-(2,4-dichlorophenyl)pyrimidine

The compound was prepared in an analogous manner to the compound ofExample 21B.f. from 5-(2,4-dichlorophenyl)isocytosine, mp. 215°-216° C.

EXAMPLE 91 2-Amino-4-methylamino-5-(2,4-dichlorophenyl)pyrimidine

This compound was prepared from the compound of Example 90 by reactionwith methylamine in ethanol, mp. 189°-90° C.

EXAMPLE 92 2-Amino-4-dimethylamino-5-(2,4-dichlorophenyl)pyrimidinehydrochloride

This compound was prepared from the compound of Example 90 by reactionwith dimethylamine in ethanol and subsequent conversion to thehydrochloride salt, mp. 297°-301° C.

EXAMPLE 93 2-Amino-4-piperidino-5-(2,4-dichlorophenyl)pyrimidinehydrochloride

This compound was prepared from the compound of Example 90 by reactionwith piperidine in ethanol and subsequent conversation to thehydrochloride salt, mp. 303° C. (dec).

Preferred among the compounds of formula (I) are the pyrimidines of theforegoing Examples 1, 2, 3, 4, 14 and 16, together with salts (inparticular, pharmaceutically acceptable salts) thereof; these bases havethe following respective two-dimensional structures. ##STR6##

    ______________________________________    TABLE of .sup.1 H NMR DATA (δ)    EXAMPLE    NO.      SOLVENT   ASSIGNMENT    ______________________________________    1        CDCl.sub.3                       7.56(d, 1H), 7.18(d, 1H), 4.65-4.50                       (br.s, 2H), 3.88(t, 4H), 2.5(t, 4H),                       2.36(s, 3H)    2        DMSO-d.sub.6                       3.06(s, 3H, --OMe), 3.8(d, 1H,                       J12.5Hz, --CH.sub.2 OMe), 3.9(d, 1H,                       J12.5Hz, --CH.sub.2 OMe), 5.98(br.s, 2H,                       --NH.sub.2), 6.1(br.s, 2H, --NH.sub.2),                       7.32(d, 1H, J2.5Hz, 6'-H), 7.78(d, 1H,                       J2.5Hz, 4'-H)    3        DMSO-d.sub.6                       7.8(d, 1H), 7.65(s, 1H), 7.36(d, 1H),                       6.33-6.23(brs, 2H), 3.68(t, 4H),                       2.32(t, 4H), 2.2(s, 3H)    4        DMSO-d.sub.6                       6.40(s, 2H), 6.55(s, 2H), 7.35(s, 1H),                       7.80(s, 1H)    5        DMSO-d.sub.6                       8.6(s, 1H), 7.49(s, 1H), 6.4-6.3(br.s,                       2H), 6.25-6.15(br.s, 2H)    6        DMSO-d.sub.6                       1.70(s, 3H), 5.75(s, 2H), 5.90(s, 2H),                       7.30(s, 1H), 7.75(s, 1H)    7        CDCl.sub.3                       7.55(d, 1H), 7.18(d, 1H), 4.75-4.58                       (br.s, 2H), 3.9-3.7(m, 8H)    8        CDCl.sub.3                       7.55(d, 1H), 7.18(d, 1H), 4.56-4.50                       (br.s, 2H), 3.2(s, 6H)    9        DMSO-d.sub.6                       7.79(d, 1H), 7.67(s, 1H), 7.36(d, 1H),                       6.47-6.27(br.s, 2H), 3.72-3.57(m, 8H)    10       DMSO-d.sub.6                       7.78(d, 1H), 7.64(s, 1H), 7.35(d, 1H),                       3.08(s, 6H)    11       CDCl.sub.3                       7.51(d, 1H), 7.17(d, 1H, 4.40-4.22                       (br.s, 2H), 3.82(t, 4H), 2.48(t, 4H),                       2.34(s, 3H), 2.0(s, 3H)    12       DMSO-d.sub.6                       8.28(s, 1H), 6.18-6.04(br.d, 4H),                       2.1(s, 3H)    13       CDCl.sub.3                       7.51(d, 1H), 7.18(d, 1H), 4.36-4.22                       (br.s, 2H), 3.16(s, 6H), 2.0(s, 3H)    14       DMSO d.sub.6                       6.10(s, 2H), 6.45(s, 2H), 7.15(d, 1H),                       7.30(t, 1H), 7.55(d, 1H)    15       DMSO-d.sub.6                       1.70(s, 3H), 5.60(s, 2H), 5.80(s, 2H),                       7.15(d, 1H), 7.30(t, 1H), 7.55(d, 1H)    16       DMSO-d.sub.6                       3.04(s, 3H, --OMe), 3.76(d, 1H,                       J12Hz, --CH.sub.2 OMe)                       3.85(d, 1H, J12Hz, --OCH.sub.2 OMe),                       5.84(br.s, 2H, --NH.sub.2), 6.05(br.s, 2H,                       --NH.sub.2), 7.22(dd, 1H, J7.5, 1.5Hz,                       6'-H), 7.38(dd, 1H, J7.5Hz, 5'-H),                       7.6(dd, 1H, J7.5, 1.5Hz, 4'-H)    17       DMSO-d.sub.6                       7.3-8.0(m, 8H), 6.0-6.1(br.s, 2H),                       5.2-5.4(br.s, 2H)    18       DMSO-d.sub.6                       4.75(2xdd, 2H, J47, 15Hz, --CH.sub.2 F),                       5.95(br.s, 2H, --NH.sub.2), 6.15(br.s, 2H,                       --NH.sub.2), 7.25(dd, 1H, J7.5, 1.0Hz,                       6'-H), 7.39(dd, 1H, J7.5Hz), 7.64(dd,                       1H, J7.5, 1.0Hz)    19       DMSO-d.sub.6                       4.43(d, 1H, J11Hz), 4.53(d, 1H,                       J11Hz), 5.95(br.s, 2H), 6.12(br.s, 2H),                       6.7(m, 2H), 6.85(dd, 1H, J7Hz),                       7.1-7.4(m, 4H), 7.55(dd, 1H, J7, 1Hz).    20       DMSO-d.sub.6                       4.4(d, 1H, J12Hz, --CH.sub.2 OPh), 4.52(d,                       1H, J12Hz, --CH.sub.2 OPh), 5.92(br.s,                       2H, --NH.sub.2), 6.12(br.s, 2H, --NH.sub.2),                       6.69(dd, 1H, J7.5, 1.0Hz, 6'-H), 6.85                       (dd, 1H, J7.5Hz, 5'-H), 7.10-7.35(m,                       5H, --OPh), 7.55(dd, 1H, J7.5, 1.0Hz,                       4'-H)    21       DMSO-d.sub.6                       7.52(s, 1H), 7.15-7.75(m, 3H),                       6.02(br.s, 4H, 2x-NH.sub.2)    25       DMSO-d.sub.6                       6.07(s, 2H), 6.25(s, 2H), 7.25(d, 1H),                       7.45(d, 1H), 7.63(s, 1H)    26       DMSO-d.sub.6                       3.88(d, 1H, J11Hz), 4.0(d, 1H,                       J11Hz), 4.3(s, 2H), 5.9(br.s, 2H),                       6.1(br.s, 2H), 7.05-7.2(m, 2H), 7.2-                       7.35(m, 4H), 7.4(dd, 1H, J8, 2.5Hz),                       7.62(d, 1H, J2.5Hz)    28       DMSO-d.sub.6                       6.25(s, 2H), 6.50(s, 2H), 7.30(s, 1H),                       7.40(d, 1H), 7.50(d, 1H)    29       DMSO-d.sub.6                       5.85(s, 2H), 6.1(s, 2H), 7.25(s, 1H),                       7.45(s, 1H), 7.7(s, 1H)    30       CDCl.sub.3                       7.53-7.12(m, 4H), 4.48-4.30(br.s, 2H),                       3.81(t, 4H), 2.46(t, 4H), 2.33(s, 3H),                       2.03(s, 3H)    32       CDCl.sub.3                       7.38(d, 1H), 7.2(dd, 1H), 7.08(d, 1H),                       8.2(br.s, 2H)    33       DMSO-d.sub.6                       7.7(d, 1H), 7.48(dd, 1H), 7.29(d, 1H),                       6.45(br.s, 2H), 6.2(br.s, 2H)    34       CDCl.sub.3                       7.5(d, 1H), 7.35(dd, 1H), 7.18(d, 1H),                       5.25(br.s, 2H), 2.44(s, 3H)    35       CDCl.sub.3                       7.52(d, 1H), 7.32(dd, 1H), 7.21(d,                       1H), 5.08(br.s, 2H), 4.66(br.s, 2H),                       2.42(s, 3H)    36       DMSO-d.sub.6                       1.9(s, 3H, 6-CH.sub.3), 2.2(s, 3H, N-Me),                       2.25-2.40(m, 4H, --N N--), 3.55-3.75                       (m, 4H, --N N--), 5.85(2H, br.s,                       --NH.sub.2), 7.2(d, 2H, J1.5Hz, 2',                       6'-H), 7.52(dd, 1H, J1.5Hz, 4'-H)    56       DMSO-d.sub.6                       7.58(dd, 1H), 7.45(dd, 1H), 7.35(d,                       1H), 7.24(br.s, 1H), 3.35(br.s, 2H),                       3.96(br.s, 2H)    57       DMSO-d.sub.6                       1.8(s, 3H), 5.8(s, 2H), 5.95(s, 2H),                       7.53(s, 1H), 7.92(s, 1H)    58       DMSO-d.sub.6                       7.78(d, 1H), 7.59(s, 1H), 7.36(d, 1H),                       6.60-6.47(br.t, 1H), 6.25-6.03(br.s,                       2H), 3.25(q, 2H), 1.1(t, 3H)    ______________________________________     In the foregoing, the signals have been abbreviated as follows: s =     singlet; d = doublet; dd = doublet of doublets; t = triplet; q =     quadruplet; m = multiplet; br.s = broad singlet; br.t = broad triplet.

Pharmacological Activity

Inhibition of Glutamate release and Inhibition of Rat Liver DHFR

Compounds of Formula (I) were tested for their effect onveratrine-evoked release of glutamate from rat brain slices according tothe protocol described in Epilepsia 27(5): 490-497, 1986. The protocolfor testing for inhibition of DHFR activity was a modification of thatset out in Biochemical Pharmacology Vol. 20 pp 561-574, 1971.

The results are given in Table 1, the IC₅₀ being the concentration ofcompound to cause 50% inhibition of (a) veratrine-evoked release ofglutamate and (b) of DHFR enzyme activity.

                  TABLE 1    ______________________________________    Compound  IC.sub.50 (μM)                             IC.sub.50 (μM)    of        Glutamate Release                             Rat Liver DHFR    Example No.              (P95 limits)   (P95 limits)    ______________________________________    1         1.18    (0.50-2.60)                                 >100    2         0.56    (0.23-1.37)                                 33     (27.00-40.00)    3         2.15    (0.90-5.10)                                 >100    4         0.33    (0.196-0.566)                                 >30    <100    5         3.50    (1.10-10.40)                                 ca.    100    6         0.70    (0.40-1.50)                                 0.51   (0.36-0.73)    7         <10.00             >10.0    8         <10.00             >10.0    9         <10.00             >100.00    10        <10.00             >100.00    11        4.80    (2.30-10.20)                                 >100.00    12        <10.00             >100.00    13        <10                >100.00    14        3.1     (2.1-4.6)  >100.00    15        2.7     (1.0-7.2)  8.7    (5.2-14.7)    16        3.2     (1.7-6.1)  >100    17        2.4     (1.00-5.80)                                 4.9    (3.90-6.20)    18        <10.00  ca.        100    19        2.6     (0.80-8.50)                                 >100.00    20        4.2     (1.20-15.30)                                 17.50  (9.80-31.40)    21        11.5    (4.80-27.60)                                 16.01  (12.05-21.282)    22        2.80    (0.80-9.80)                                 23.800 (9.00-61.00)    23        8.70    (2.60-29.10)                                 20.940 (9.00-61.00)    24        2.10    (0.90-4.80)                                 15.10  (11.00-20.70)    25        4.10    (1.10-15.50)                                 >100.00    26        ca.     3.00       c10.00    27        ca.     10.00      >100.00    28        4.6     (1.60--13.30)                                 46.10  (14.30-148.90)    29        1.57    (0.94-2.62)                                 0.53   (0.348-0.812)    ______________________________________

Toxicological Example

The compound of Example 1 has been administered intravenously to groupsof six male and six female Wistar rats once daily at dose levels of upto 15 mg/kg/day. The no observsed effect dose was 2.5 mg/kg/day.

The compound of Example 2, has been tested in both rats and dogs. Inrats the no observed effect dose was 2.5 mg/kg/day and in dogs, the noobserved effect dose was 14 mg/kg/day.

Pharmaceutical Formulation Example

    ______________________________________    Tablet:            INGREDIENT    ______________________________________    A:        Compound of Example 1                                 150    mg )              Lactose            200    mg )              Maize Starch       50     mg )              Polyvinylpyrrolidone                                 4      mg )              Magnesium Stearate 4      mg )    ______________________________________     ) = contents per tablet.

The drug was mixed with the lactose and starch and granulated with asolution of the polyvinylpyrrolidone in water. The resultant granuleswere dried, mixed with magnesium stearate and compressed to givetablets.

B: INJECTION (I)

The salt of the compound of Formula I was dissolved in sterile water forinjection.

INTRAVENOUS INJECTION FORMULATION (II)

Active ingredient 0.20 g

Sterile, pyrogen-free phosphate buffer (pH9.0) to 10 ml

The compound of Example I as a salt is dissolved in most of thephosphate buffer at 35°-40° C., then made up to volume and filteredthrough a sterile micropore filter into sterile 10 ml glass vials(Type 1) which are sealed with sterile closures and overseals.

In the following Examples, the active compound maybe any compound offormula (I) or pharmaceutically acceptable salt thereof.

C: Capsule formulations

Capsule Formulation A

Formulation A may be prepared by admixing the ingredients and fillingtwo-part hard gelatin capsules with the resulting mixture.

    ______________________________________                      mg/capsule    ______________________________________    (a) Active ingredient                        250    (b) Lactose B.P.    143    (c) Sodium Starch Glycollate                         25    (d) Magnesium Stearate                         2                        420    ______________________________________

    ______________________________________                    mg/capsule    ______________________________________    (a) Active ingredient                      250    (b) Macrogel 4000 BP                      350                      600    ______________________________________

Capsules may be prepared by melting the Macrogel 4000 BP, dispersing theactive ingredient in the melt, and filling two-part hard gelatincapsules therewith.

Capsule Formulation B (Controlled release capsule)

    ______________________________________                      mg/capsule    ______________________________________    (a) Active ingredient                        250    (b) Microcrystalline Cellulose                        125    (c) Lactose BP      125    (d) Ethyl Cellulose  13                        513    ______________________________________

The controlled-release capsule formulation may be prepared by extrudingmixed ingredients (a) to (c) using an extruder, then spheronising anddrying the extrudate. The dried pellets are coated with ethyl cellulose(d) as a controlled-release membrane and filled into two-part hardgelatin capsules.

Syrup Formulation

    ______________________________________    Active ingredient     0.2500  g    Sorbitol Solution     1.5000  g    Glycerol              1.0000  g    Sodium Benzoate       0.0050  g    Flavour               0.0125  ml    Purified Water q.s. to                          5.0     ml    ______________________________________

The sodium benzoate is dissolved in a portion of the purified water andthe sorbitol solution added. The active ingredient is added anddissolved. The resulting solution is mixed with the glycerol and thenmade up to the required volume with the purified water.

Suppository formulation

    ______________________________________                           mg/suppository    ______________________________________    Active ingredient (63 μm)*                              250    Hard Fat, BP (Witepsol H15 - Dynamit Nobel)                             1770                             2020    ______________________________________     *The active ingredient is used as a powder wherein at least 90% of the     particles are of 63 μm diameter or less.

One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C. maximum. The active ingredient is sifted through a 200 μm sieve andadded to the molten base with mixing, using a silverson fitted with acutting head, until a smooth dispersion is achieved. Maintaining themixture at 45° C., the remaining Witepsol H15 is added to the suspensionwhich is stirred to ensure a homogenous mix. The entire suspension isthen passed through a 250 μm stainless steel screen and, with continuousstirring, allowed to cool to 40° C. At a temperature of 38°-40° C. 2.02g aliquots of the mixture are filled into suitable plastic moulds andthe suppositories allowed to cool to room temperature.

We claim:
 1. A method of treating a mammal who has suffered physicalinjury or trauma of the spinal cord or brain, which method comprisesadministering to said mammal a nontoxic effective amount of4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidineor a pharmaceutically acceptable acid addition salt thereof.
 2. Themethod of claim 1 in which an inorganic acid said salt is administered.3. The method of claim 1 in which an organic acid said salt isadministered.
 4. The method of claim 1 in which said salt formed from anacid selected from the group consisting of hydrochloric, hydrobromic,sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,succinic, fumaric, maleic, oxaloacetic, ethanesulphonic,p-toluenesulphonic, benzenesulphonic and isethionic acids isadministered.
 5. The method of claim 1 in which4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidinemethanesulphonate is administered.
 6. The method of claim 1 in which the4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-tridhlorophenyl)pyrimidineor salt thereof is administered orally.
 7. The method of claim 1 inwhich the4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidineor salt thereof is administered by injection.
 8. The method of claim 1in which the4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidineor salt thereof is administered intravenously.
 9. The method of claim 1in which the mammal is a human.
 10. The method of claim 9 in which 35 to1,050 mg of4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidineis administered per day to an adult human.
 11. A method of treating ahuman who has suffered physical injury or trauma of the spinal cord orbrain, which method comprises administering to said human apharmaceutical formulation comprising a pharmaceutically acceptablecarrier and a non-toxic effective amount of4-amino-2-(4-methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidineor a pharmaceutically acceptable acid addition salt thereof.